TGF the perpetrator of immune suppression by regulatory cells by MikeJenny


									TGF- : the perpetrator of immune suppression by regulatory
  T cells and suicidal T cells
            Sharon M. Wahl,1 Jennifer Swisher, Nancy McCartney-Francis, and Wanjun Chen
            Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of
            Health, Bethesda, Maryland

Abstract: Innate and adaptive immunity function                         As a secreted cytokine/growth factor, TGF- regulates mul-
to eliminate foreign invaders and respond to injury                  tiple fundamental cellular processes including growth, migra-
while enabling coexistence with commensal mi-                        tion, adhesion, extracellular matrix formation, and apoptosis.
crobes and tolerance against self and innocuous                      As initially reported more than a decade ago, TGF- is a potent
agents. Although most often effective in accom-                      chemotactic factor, recruiting monocytes, neutrophils, and
plishing these objectives, immunologic processes                     lymphocytes at femtomolar concentrations [1–3], which pro-
are not fail-safe and may underserve or be exces-                    vided the first evidence of its potential involvement in immune
sive in protecting the host. Checks and balances to                  and inflammatory processes. Rapidly released by platelets at a
maintain control of the immune system are in place                   site of injury or infection or by activated inflammatory cells
and are becoming increasingly appreciated as tar-                    themselves, TGF- not only influences recruitment but also
gets for manipulating immunopathologic re-                           adhesion and activation of circulating leukocytes [4 – 6], en-
sponses. One of the most recognized mediators of                     gaging an immunologic cascade for sequestration of the foreign
immune regulation is the cytokine transforming                       agent, debridement, and tissue repair, essential to restoration
growth factor- (TGF- ), a product of immune and                      of tissue integrity. Secreted as a latent molecule, TGF- is
nonimmune cells. Emerging data have unveiled a                       activated from its latent complex by proteolytic and nonpro-
pivotal role for TGF- as a perpetrator of suppres-                   teolytic mechanisms [7, 8] to bind to and trigger its cognate
sion by CD4 CD25 regulatory T (Treg) cells and                       receptors on target cells. Once activated, TGF- elicits its
in apoptotic sequelae. Through its immunosup-                        cellular effects, including leukocyte chemotaxis, in a dose-
pressive prowess, TGF- effectively orchestrates                      dependent manner through cell-surface TGF- serine/threo-
resolution of inflammation and control of autoag-                     nine type I and II (TßRI and TßRII) receptors and engagement
gressive immune reactions by managing T cell an-                     of a Smad (transcription factor activated by TGF- )-dependent
ergy, defining unique populations of Treg cells,                      signal [9]. Ligation of constitutively phosphorylated TßRII
regulating T cell death, and influencing the host                     enlists and phosphorylates TßRI, initiating signal transduction
response to infections. J. Leukoc. Biol. 76: 15–24;                  powered through a novel family of Smad proteins. The acti-
2004.                                                                vated TßRII–TßRI complex phosphorylates Smad2 and/or -3,
                                                                     which dissociate from the receptor complex and partner with
Key Words: immunoregulation apoptosis leishmania                     Smad4 in a heteromeric complex that translocates into the
                                                                     nucleus as a transcription factor for TGF- -responsive genes
                                                                     [10]. Although Smad2 deletion is embryologically lethal [11],
INTRODUCTION                                                         the Smad3 null mice exhibit a phenotype, which in some ways
                                                                     parallels the TGF- knockout mice [12]. Smad3 null mice
The genesis of inflammation or pathogenesis of chronic inflam-         develop inflammation, particularly in mucosal tissues, and
matory diseases, whether initiated by trauma, pathogens, or          chronic infections, in part, as a result of the defective chemo-
antigens, depends on the trafficking of inflammatory cells to the      taxis of Smad3 null leukocytes toward TGF- [9, 12]. However,
site of induction, their local activation, and release of media-     as not all TGF- signaling occurs via Smad3, the null mice live
tors to recruit and activate additional populations. The precise     longer with less-severe organ inflammation than the TGF- 1
molecular and microenvironmental mechanisms dictating this           null mice [13–15].
cellular infiltration and local retention continue to be deci-           As a counterbalance to the potent consequences of the
phered, but equally compelling is the definition of the cells and     TGF- signal-transduction scenario, there exist intracellular
mediators involved in the suppression of inflammation for the         Smad proteins with inhibitory activity. Smad6 and -7 partici-
ultimate restoration of immune homeostasis. It is striking that      pate in negative-feedback loops that may regulate the intensity
one of the mediators orchestrating the genesis of inflammation
is, paradoxically, also pivotal in the resolution of the response.
How transforming growth factor- (TGF- ) drives and serves               1
                                                                          Correspondence: OIIB, NIDCR, NIH, Building 30, Rm. 320, 30 Convent
as a brake for inflammation and immune responses remains              Drive, MSC4352, Bethesda, MD 20892-4352. E-mail:
enigmatic, but emerging studies paint a unique portrait of this         Received November 5, 2003; revised December 23, 2003; accepted January
immunoregulatory molecule.                                           9, 2004; doi: 10.1189/jlb.1103539.

                                                                           Journal of Leukocyte Biology Volume 76, July 2004 15
or duration of TGF- responses by binding to TßRI and dis-             though exogenous protein and/or gene transfer of TGF- may
engaging activation of other Smads [16, 17]. Smad7 expression         have potential in the treatment of chronic inflammatory and
is rapidly elevated in response to interferon- (IFN- ) but also       autoimmune diseases, these approaches are not without liabil-
TGF- , resulting in down-regulated Smad2/3 activation and             ity as a result of the ubiquitous presence of TGF- receptors.
blunting of the TGF- signal [18]. As components of a more             Consequently, the search continues for potential strategies to
complex network, Smad proteins also intersect with nuclear            manipulate endogenous TGF- and control the genesis of
factor- B and mitogen-activated protein kinase (MAPK) sig-            immune disorders. One of the earliest, appreciated approaches
naling pathways [19, 20] to mediate downstream TGF- regu-             to manipulation of immunopathogenesis through TGF- in-
latory circuits [21].                                                 volves the induction of oral tolerance.
   With the initial barrage of inflammatory mediators, includ-
ing TGF- , at a site of injury/infection, a chain reaction is set
in motion, with recruitment, proliferation, and activation of the     ORAL TOLERANCE
cellular participants. Release of TGF- by leukocytes and
local cell populations, in turn, induces newly emigrated, im-         The gastrointestinal tract, continually confronted with self and
mature cells to generate additional cytokines including tumor         nonself antigens in its lumen, must rely on tolerizing mecha-
necrosis factor (TNF- ), interleukin (IL)-l , and chemokines          nisms to prevent constant engagement of the mucosal immune
to perpetuate the response. This powerful promotion of inflam-         system. Recognizing this evolutionary adaptation, investigators
mation is dependent not only on TGF- receptor capacity but            attempted to mimic the response by oral delivery of low-dose
also on the state of cellular differentiation and the micromilieu.    antigens and documented subsequent hyporesponsiveness to
It is important that resting cells are often turned on/activated      the ingested proteins [29]. The suppression of specific antigen
when the TGF- ligand connects with its receptor, whereas              as well as bystander antigen responses occurs by multiple
once activated, inflammatory cells typically become suscepti-          mechanisms, but the generation of a population of Th3 cells
ble to inhibition by TGF- , reflecting the ability of TGF- to          [30] appears paramount. Among the molecules and strategies
operate as a switch factor, dependent on context [22]. Consis-        used by these cells to orchestrate immune suppression and
tent with its complex and even apparent opposing effects in           tolerance is TGF- [30 –34]. The efficacy of oral tolerance is
immunity, local expression or injection of TGF- generally             linked to the dose and kinetics of antigen delivery in that
favors its proinflammatory profile, and neutralization of this          low-dose antigen-feeding favors generation of regulatory T
excess protein may ameliorate chronic inflammatory destruc-            (Treg) cells, which mainly produce TGF- but also IL-4 and
tive and/or fibrotic pathogenesis [23–26].                             IL-10, whereas high-dose antigen drives anergy and/or apopto-
   Although cognizant of the dramatic role of TGF- in the             sis of antigen-specific Th1 as well as Th2 cells but not neces-
onset and evolution of an immune/inflammatory response, this           sarily TGF- -producing Th3 cells [30, 32]. From an interven-
review will focus on the expanding appreciation for TGF- as           tional standpoint, oral administration of auto-antigens or non-
a crucial agent in dimming the immune response and averting           self antigens can prevent and/or suppress experimental models
the harmful pathogenesis associated with unresolved inflam-            of autoimmunity, chronic inflammation, and also transplanta-
mation. As TGF- molecules are highly conserved, it is likely          tion rejection [29, 32]. In orally tolerized animals, peripheral
that this cytokine represents an evolutionary adaptation de-          lymphoid tissues express increased levels of TGF- , which is
signed to protect the host from overexuberant and tissue-             reflected by elevated, circulating TGF- and a corresponding
destructive, inflammatory events. Clearly, in its ability to limit     decrease in serum TNF- and reduced clinical severity of
inflammation and modify innate and adaptive immunity,                  disease [32]. Despite the success of inducing oral tolerance in
TGF- has no equal.                                                    animal models, clinical trials evaluating the impact of orally
                                                                      induced tolerance in humans have been less-clearly beneficial,
                                                                      likely reflecting the differences between inbred mice and com-
TGF- AS AN INHIBITOR OF INFLAMMATION                                  plex disease processes in man [29, 31] and warranting contin-
AND IMMUNITY                                                          ued investigation.

Based on our understanding that TGF- can suppress effector
T cell [T helper cell type 1 (Th1) and Th2] and activated             T CELL TARGETS OF TGF-                   SUPPRESSION
macrophage functions [6, 27] and that most experimental au-
toimmune diseases are initiated and mediated by T cells,              Whether TGF- is augmented endogenously via induction of
particularly Th1 cells, and are effected by phagocytic cells [6],     oral tolerance or other routes of inducement or is administered
a resurgence of enthusiasm for TGF- has occurred. Admin-              exogenously, its ability to regulate the functional repertoire of
istration of exogenous TGF- protein systemically by gene              T cells may be quite diverse depending on the local environs
transfer or by manipulation of T cells with TGF- before                                               ¨
                                                                      and whether the T cells are naıve, differentiated, or activated.
transfer, can prevent or inhibit experimental autoimmune dis-         The heterogeneity in response may reflect, in part, the level of
eases (reviewed in refs. [6, 28]). As evident in vitro, the effects   expression of TGF- receptors, which are up-regulated when T
of in vivo TGF- administration on the development of auto-            cells are activated [35, 36]. Moreover, TGF- itself increases
immune pathology depend on multiple parameters, including             receptor levels, implicating a feedback loop favoring suppres-
concentration, route, and time of delivery, presence of other         sion [23]. The critical nature of the TGF- –TßRII signaling
cytokines, and the activation status of cellular targets. Al-         pathway in regulating T cell function has been documented in

16   Journal of Leukocyte Biology Volume 76, July 2004                                                 
transgenic mice in which expression of a dominant-negative          tion in antigen-presenting cells (APC) [46, 47]. TGF- also
TßRII under a T cell-specific promoter or overexpression of a        counters the ability of macrophage or dendritic cell (DC)-
dominant-negative TßRII on T cells culminates in spontaneous        derived IL-12 to activate T cell Janus tyrosine kinase–signal
T cell activation and Th1 and Th2 cytokine release [37, 38].        transducer and activator of transcription signaling pathways
These transgenic mice may develop autoimmune, inflammatory           [48, 49]. Confirming this opposing activity between IFN-
disease, characterized by cellular invasion of several organs       and TGF- , there is a profound augmentation of IFN- and
such as lung, colon, stomach, pancreas, and/or kidney. Al-          its downstream impact, particularly on macrophages, in
though the receptor-defective mice do not display symptoms          mice lacking TGF- [50], which is pivotal in controlling
until 3– 4 months of age, distinct from the phenotype of            macrophage-inducible nitric oxide synthase (iNOS), induc-
TGF- 1 null mice, their immunologic, functional repertoire is       ible cyclooxygenase, and matrix metalloproteinases, all of
clearly compromised. In humans, patients with Sezary syn-           which become incendiary in its absence. These and related
drome, whose CD4 T cells exhibit decreased surface TßRII,           complex immunoregulatory circuits may influence induction
also have reduced responsiveness to the growth-inhibitory ef-       of Treg cells and maintenance of immune suppression.
fects of TGF- 1 and consequently, uncontrolled T cell prolif-
eration [39].
   The cytokine milieu is another factor underlying T cell          Treg CELLS
vulnerability to the impact of TGF- , as exemplified by the
ability of IL-2 to significantly perturb the inhibitory influence     Beyond Th3 cells implicated in oral tolerance, additional pop-
of TGF- [6]. IL-2 supports T cell proliferation [40], and           ulations of T cells exhibit immunoregulatory and tolerogenic
TGF- , by inhibiting T-bet (Th1) or GATA3 (Th2) transcrip-          functions, including T regulatory type 1 (Tr1) and CD4 T
tion factor expression [38, 41], suppresses proliferation and       cells constitutively expressing IL-2 receptor (IL-2R ) chain
cytokine responses. In a microenvironment replete with IL-2,        (CD4 CD25 Treg) [51, 52]. Two of these populations, Th3
typical of the initial phase of inflammation, early viral infec-     and Tr1, manage their immunosuppressive actions mainly
tion, or acute transplant rejection, when antigen-specific T         through the release of soluble factors, including TGF- and/or
cells are undergoing priming or activation, TGF- may foster         IL-10 [31, 53]. Moreover, these cells do not function indepen-
their growth and differentiation [42, 43]. In contrast, should      dently but rather network to mediate suppression. For example,
IL-2 be selectively depleted, as may occur in a tumor site,         Treg may govern the fate and distribution of Th3 and Tr1,
virus-induced immunodeficiency, or in autoimmune disease             according to their complement of adhesion receptors. 4 7
remission, antigen-specific T cell responses are likely blunted      Treg might preferentially home to mucosal sites and convert
by a micromilieu rich in active TGF- . Suppression of prolif-       CD4 T cells into IL-10-producing Tr1-like cells, whereas
eration results not only from diminished IL-2 but likely also via     4 1 Treg, targeted to inflamed tissues (vascular cell adhe-
TGF- suppression of c-Myc and enhancement of cell-cycle             sion molecule ), might drive development of TGF- -producing
inhibitors, p15INK4b and p21CIP1 [44]. Likewise, a reciprocal       Th3-like cells, passing on the role of suppressors in a process
relationship exists between IFN- and TGF- , which involves          of “infectious tolerance” [54] (Fig. 1).
IFN- enhancement of inhibitory Smad7 expression to block               This unusual population of Treg mediates suppression via a
TGF- signaling [45, 46]. In turn, TGF- may directly inhibit         distinct cell contact-dependent mechanism involving cell
IFN- as well as IL-2 production by T cells or indirectly target     membrane-bound TGF- , cytotoxic T lymphocyte antigen
IFN- by suppressing CD40 expression and/or IL-12 produc-            (CTLA)-4, and glucocorticoid-induced TNFR (GITR) [36, 52–

                                                                                      Fig. 1. Generation and regulation of Treg cells. CD4
                                                                                      T cells, triggered by antigen and APC, progress to Th1
                                                                                      (IFN- ) and/or Th2 (IL-4) mediators of immunity.
                                                                                      CD4 CD25 Treg cells are generated in the thymus or
                                                                                      converted from CD4 CD25– responder T cells to gen-
                                                                                      erate TGF- and mediate suppression of CD4 CD25–
                                                                                      responder T cell proliferation and cytokine production.
                                                                                      Suppression involves cell contact between TGF- Tß-
                                                                                      RII Treg and activated responder cells, which become
                                                                                      TßRII . Treg may also orchestrate Th3 and/or Tr1
                                                                                      activity in target tissues. CD4 responder cells may be
                                                                                      released from Treg suppression when APC, triggered
                                                                                      through Toll-like receptors (TLR), produce IL-6 and an
                                                                                      unknown factor(s) (Factor X). The balance between ac-
                                                                                      tivation (green arrow) and suppression (red arrow) un-
                                                                                      derlies development of immunity and its resolution.

                                                                                 Wahl et al. Immune suppression by TGF-                  17
55]. As regulators, Treg cells suppress induction and activity of   APC function as Treg instructors represents an understud-
Th1 and Th2 lymphocytes, promote tolerance, and diminish            ied but important aspect of Treg activities, and recent
antitumor defense. Initial studies uncovering this potent CD4       evidence suggests that APC coordinate recruitment and/or
immunoregulatory T cell population capable of preventing            generation scenarios including Foxp3 expression [61, 73,
autoaggressive behavior defined them by their expression of          75], but in turn, Treg may dictate APC functions [76].
CD25, origination from the thymus, and small numbers ( 10%          Clearly, Treg cells do not function in isolation, and once
of CD4 T cells) [51]. Depletion of Treg before transfer of          activated, APC also may limit Treg-suppressive function
CD4 T cells into immunocompromised mice resulted in a               following TLR ligation-induced release of IL-6 and/or other
high incidence of organ-specific, autoimmune disease [51].           molecules [77] (Fig. 1), demonstrating differential roles for
More recently, Treg cells have been shown to express a unique       APC depending on their activation status. TLR, newly rec-
profile of markers including CTLA-4 [56 –58] and GITR [59,           ognized on Treg [78], may contribute to the regulation of
60], both of which enable regulation of the regulators [34, 61]     these suppressor cells in the context of infectious patho-
(Fig. 1). Not only are these Treg themselves anergic to T cell
receptor (TCR) stimulation, but they markedly suppress pro-
                                                                       Although the in vitro dependency of Treg suppression on
liferation of CD4 CD25– antigen-responsive T cells, in large
                                                                    TGF- is compelling, immune suppression mediated by
part by blocking production of IL-2 [52] and in vitro, Treg-
                                                                    Treg in vivo clearly requires TGF- , in that administration
mediated suppression can be overcome by addition of IL-2 and
                                                                    of an antibody to TGF- blocks protection from colitis,
anti-CD28 [36, 52]. Treg cells need TCR engagement for
optimal suppressive competence, but once stimulated, they           otherwise afforded by transfer of a mixture of CD45RBhi and
suppress T cell activation in an antigen-nonspecific manner          CD4 CD25 CD45RBlow cells [56]. Moreover, in a type 1
[52]. The recognized importance of Treg has propelled rapid         diabetes model, CD8 T cells bearing a dominant-nega-
and intense investigations to delineate the molecules and sig-      tive TßRII transgene were functionally incapable of re-
nal pathways that orchestrate their recruitment, activation, and    sponding to Treg suppression, resulting in diabetes progres-
function in anticipation of potential therapeutic insight.          sion [63].
   In defining the molecular mechanisms underlying cell-con-            Although the debate over the mechanism of Treg suppres-
tact dependency, at least in vitro, this population was recently    sion is resolving, the source and pathways by which these
shown to express cell-surface TGF- in its active and/or latent      Treg cells are generated and developed remain elusive.
form [36, 62– 64] and TßRII [36], whereas CD4 CD25– T cells         Previous evidence favored the thymus as the incubator for
(responder cells) are virtually negative for membrane TGF- or       Treg and suggested that little could be accomplished in
TßRII, at least until after TCR activation [34, 36]. Coexpres-      attempting to manipulate these cells in the periphery for
sion of active TGF- and TßRII on Treg may account not only          interventional tactics. However, in exciting new data, it
for their own anergic state but also the functional interaction     appears that the necessary stimuli by which peripheral
between their membrane-displayed TGF- and the inducible             CD4 T cell populations can be converted to functional and
TßRII, which appear on responder CD4 and CD8 T cells                phenotypic Treg, at least in vitro, are now being defined [75,
following TCR activation, a pivotal maneuver underlying cell        79, 80]. When coactivated with TCR and TGF- ,
contact-dependent suppression [36] (Fig. 1), although this          CD4 CD25– T cells begin to express the transcription fac-
mechanism is not uniformly accepted [65]. The indispensabil-        tor, forkhead/winged helix (Foxp3), which appears to be a
ity of TßRII ligation on responder cells was convincingly           master regulator for their transition into CD4 CD25 T
documented in antigen-reactive CD8 T cells bearing a dom-           suppressor cells [81– 83]. TCR activation of CD4 re-
inant-negative TßRII, which were incapable of being sup-            sponder T cells in the presence of defining concentrations of
pressed by Treg [63].                                               TGF- does not trigger expansion of small numbers of Treg
   As anticipated, cells with such potent regulatory activity
                                                                    cells in the population but rather converts the CD4 re-
must have their own set of regulators. Treg constitutively
                                                                    sponder T cells to CD4 CD25 Foxp3 T cells, which are
express CTLA-4 [56 –58], and ligation of CTLA-4 induces
                                                                    not only anergic but also suppress antigen-driven responder
production of TGF- [66 – 68] to enhance their suppressive
                                                                    cell proliferation. More importantly, transfer of these con-
prowess. Conforming to this role of CTLA-4 as a promoter of
                                                                    verted Treg into mice immunized and challenged with house
suppression, anti-CTLA-4 injection blocks Treg suppres-
sion of murine colitis [56]. In contrast to CTLA-4-aug-             dust-mite allergen resulted in a striking reduction in lung
mented Treg function, GITR represents a counterbalance,             infiltrates, mucus production, and asthma pathogenesis [75].
and signaling through GITR blunts or reverses suppression           These deliberate mechanisms to drive Treg commitment in
[59, 60], although the functional mechanism remains elu-            peripheral T cells are consonant with recent data, docu-
sive. Our own studies indicate that GITR stimulation in Treg        menting increased numbers of Treg cells bearing TGF-
may interfere with the TGF- signaling cascade (W. Chen et           associated with control of autoaggressive behavior in vivo
al., unpublished). In addition to IL-2, CTLA-4, and GITR,           [63]. With the evolving potential to induce Treg upon de-
Treg are also functionally influenced by less-selective mol-         mand, it becomes feasible to consider therapeutic manipu-
ecules, among them CD28, CD154, TNF-related cytokine-               lation of immunopathologic sequelae. Boosting Treg may
induced molecule, inducible costimulator, CCR4, CCR8,               control autoimmune diseases and promote transplant sur-
and CCR5 [69 –74], indicating that multiple mechanisms              vival, whereas reducing Treg may be instrumental in tumor
are probably operative in their education and control. How          rejection, vaccination, and pathogen clearance.

18   Journal of Leukocyte Biology Volume 76, July 2004                                            
CLEARANCE OF APOPTOTIC CELLS IN                                                  monocyte chemoattractant protein-1, to further reduce leuko-
IMMUNE RESOLUTION                                                                cyte recruitment to the site of inflammation. Not only phago-
                                                                                 cytosing macrophages but apoptotic T cells themselves spew
In addition to immune suppression by Treg cells, resolution of                   out latent as well as active TGF- [87] and IL-10 [88] (Fig. 2).
the host response demands clearance of the inflammatory cells                     Elevated TGF- in the local tissue site, beyond promoting
responsible for maintaining and/or amplifying the response,                      resolution of inflammation, may also contribute to tissue repair
which if excessive, can lead to tissue damage and pathogene-                     and if unchecked, promote fibropathology. Emphasizing the
sis. Whereas necrotic cell death results in the unleashing of                    on-off switch analogy, TGF- down-regulates expression of
intracellular molecules that contribute to an inflammatory mi-                    CD36, one of the receptors involved in recognition and clear-
lieu, cells undergoing apoptotic demise expose recognition                       ance of apoptotic cells [90], which may function to resolve the
molecules leading to their speedy clearance by phagocytes                        resolution.
before spillage of their cellular contents into the surrounding                     Introduction of apoptotic cells into an inflammatory lung
tissue. Apoptotic cells suppress production of inflammatory                       model reportedly ameliorated inflammatory cytokine produc-
mediators such as TNF- , IL-1 , and IL-12 by the engulfing                        tion and leukocyte recruitment [85]. Furthermore, simple lipid
macrophages in vitro and in vivo [84, 85]. However, simple                       vesicles bearing phosphatidylserine could mimic this thera-
neutrality of apoptotic clearance could never explain why                        peutic effect, apparently as a result of their ability to elicit
apoptosis-inducing treatments such as UV irradiation and X-                      TGF- release from lung macrophages. Nonetheless, injection
rays ameliorate inflammatory conditions [86, 87]. This is be-                     of apoptotic cells into the peritoneal cavity caused immediate
cause the act of apoptotic cell ingestion is actively anti-inflam-                neutrophil recruitment [91], signifying a rapid but transient,
matory, as the recognition event triggers a unique regulatory                    proinflammatory response. It stands to reason that immediate
pathway that further dampens inflammation and immunity [84,                       down-regulation of inflammation is not always in the best
87]. Recognition of the phospholipid, phosphatidylserine,                        interest of the host, and there is evidence that macrophages
newly emergent on the apoptotic cell surface, by a receptor(s)                   read a complex combination of signals to make this discrimi-
on the phagocytic cell can serve as a switch to direct pro- or                   nation. In this regard, although presentation of apoptotic cells
anti-inflammatory sequelae and/or the conversion from an in-                      to macrophages induces a completely disparate panel of cyto-
nate to an adaptive immune response through the production of                    kines than does engagement of TLR with lipopolysaccharide or
TGF- , IL-10, and/or prostaglandin E2 (PGE2) [84, 85, 87, 88]                    other ligands, combinations of these signals elicit temporally
(Fig. 2). Unequivocally, TGF- represents one of the central                      complex ensembles of pro- and anti-inflammatory mediators,
instigators of this anti-inflammatory milieu [84, 87]. In addition                depending on the ligands and order of addition [92]. However,
to the profiles of T cell and macrophage suppression described                    where initial differences in signals and their amplitude may
above, TGF- also stifles Fc receptor for immunoglobulin                           lead the immune response down different paths, all roads lead
G-mediated inflammation by down-regulating the common                             to TGF- in the end [93].
subunit in myeloid cells [89] and inhibits chemokines, such as                      T cell apoptosis remains one of the major mechanisms
                                                                                 underlying self-immune tolerance and homeostasis, and
                                                                                 TGF- influences the life and death decisions of T lympho-
                                                                                 cytes [87, 93, 94]. The TGF- 1 null mouse is doubly plagued,
                                                                                 as there is an enormous increase in T cell apoptosis, but when
                                                                                 faced with this overwhelming phagocytic burden, neither the
                                                                                 macrophages nor the apoptotic T cells can release TGF- 1 to
                                                                                 quell the storm. TGF- 1-deficient T cells manifest spontane-
                                                                                 ous activation and proliferation, and multiple organs, notably
                                                                                 heart and lungs, become invaded by burgeoning numbers of
                                                                                 these cells, which continue to accumulate until the organ
                                                                                 structure and function are compromised. This inability to clear
                                                                                 activated immune cells undergoing apoptosis with the corre-
                                                                                 sponding release of requisite, suppressive molecules amplifies
                                                                                 autoaggression and documents the nonredundancy for TGF-
                                                                                 in this aspect of the immune response. In this deficiency lies
                                                                                 the crux of the inability of the mutant mice to resolve their
                                                                                 unrelenting and lethal inflammatory response.
Fig. 2. Apoptosis of T cells and their clearance coordinates suppression and        Dramatically, injection of anti-CD3 into TGF- 1 null mice
resolution of immune responses. T cells, once activated, express enhanced
levels of surface molecules/receptors that invoke apoptosis in a process of
                                                                                 targets the already-activated T cells and amplifies and accel-
activation-induced cell death (AICD). Apoptotic T cells flip intracellular        erates their death. As a result of the double-whammy of
phosphatidylserine onto the outer leaflet of their membranes, making them         TGF- 1 deficiency in this scenario, a sublethal dose of anti-
recognizable for clearance by phagocytic cells, and also release TGF- as their   CD3 is lethal in all null mice compared with complete survival
final suicidal act. Recognition and phagocytosis of apoptotic T cells signal      of wild-type TGF- -sufficient littermates [95]. The balance
macrophages to spew out substantial TGF- , which together with IL-10 and
PGE2, mediates immune suppression. Deficiency in TGF- results in unre-
                                                                                 among sufficient apoptosis of activated, “dangerous”, and/or
solved inflammation and immunopathologic sequelae. MHC, Major histocom-           damaged lymphocytes and release of sufficient levels of anti-
patibility complex.                                                              inflammatory cytokines during their clearance are prerequi-

                                                                                              Wahl et al. Immune suppression by TGF-          19
sites to restore homeostasis and function of the immune system.      infections [101]. In fact, leishmania parasites may use TGF-
When uncoupled from the secretion of TGF- , phagocytosis of          as an escape mechanism [104]. Using parasite-derived cathep-
apoptotic lymphocytes can no longer prevent the development          sins to activate TGF- , leishmania species may increase local
of uncontrolled inflammation and autoimmune-like diseases.            concentrations of active TGF- to modulate local iNOS and
   Defects in apoptotic cell clearance have been directly linked     arginase levels, thereby providing a survival advantage for the
to persistent inflammatory and autoimmune conditions in hu-           parasite [105]. Exogenous TGF- , whether administered as
mans [96 –98]. For example, patients with genetic defects in         recombinant protein or via adenoviral vector, promotes leish-
the phagocyte reduced nicotinamide adenine dinucleotide              mania infection in resistant mice, associated with elevated
phosphate-oxidase system, whose neutrophils are resistant to         IL-10 [104, 106]. Furthermore, treatment of susceptible strains
apoptosis and macrophages are severely compromised in their          of mice, such as BALB/c, with antibodies to TGF- results not
ability to produce anti-inflammatory mediators such as TGF- ,         only in a rejuvenated Th1 response, to the detriment of their
suffer not only from recurrent, life-threatening infections but      typical, dominant Th2-nonprotective response, but also resis-
must also endure sterile inflammation and chronic granuloma-          tance to infection [104, 107]. This increased resistance follow-
tous disease [98]. This pathology is most likely a consequence       ing depletion of TGF- could be traced to an elevation in NO
of post-apoptotic secondary necrosis, in addition to the lack of     [108], consistent with the critical influence of TGF- during
immunosuppression normally generated by successful clear-            chronic stages of L. major infections. In this same vein, abro-
ance of apoptotic cells in the first place. In some ways similar      gation of TGF- signaling by expression of a dominant-nega-
to the TGF- -deficient mouse, impairment of cell-death path-          tive TßRII transgene in T cells generates a more effective Th1
ways, combined with inadequate TGF- release associated               response to control leishmaniasis in susceptible BALB/c mice,
with clearance, deliver a one-two punch of unchecked inflam-          overshadowing their otherwise nonprotective Th2 response
mation and pathogenesis.                                             [38].
                                                                        However, in the context of this parasitic disease, as in most
                                                                     of its kaleidoscope of activities, TGF- is not all bad. Host-
TGF- ALTERS HOST RESPONSE TO                                         derived TGF- , by dampening the host response to leishmania,
PATHOGENS                                                            also fosters maintenance of protective immunity. Recently,
                                                                     Treg cells have been implicated in the persistence of cutaneous
Although the suppressive role of Treg and apoptotic cell clear-      L. major infection in resistant C57BL/6 mice [109], necessary
ance are essential in regulation and resolution of innate and        for durable protection. In this parasitic disease, Treg cells, by
adaptive immune responses, excess or uncontrolled suppres-           partially suppressing the protective Th1 response, limit the
sion may also be problematic, in that tumors, acquired immune        antiparasitic response, thus enabling maintenance of a residual
deficiencies, and infectious pathogens may benefit from aber-          pocket of parasites necessary for an effective secondary-im-
rant suppression. Unregulated apoptosis or Treg-mediated sup-        mune response. Depletion of Treg in resistant mice enhanced
pression may prevent clearance of certain persistent bacterial       Th1 development with elimination of the parasites and loss of
and viral infections, whereas TLR-dependent blockade of Treg         protection from secondary challenge. In contrast, adding to the
suppression by DC [77] may promote pathogen clearance or             complexity, Treg depletion in susceptible BALB/c mice pro-
prolong the host response. Consequently, the host response to        moted Th2 development and exacerbated the infection [110].
certain pathogens may be compromised by a constellation of           These studies emphasize that contextually, Treg cells are not
events associated with suppressive dominance, underscoring           only essential for controlling parasitic infections but are also
the need to understand and regulate not only this powerful           critical for maintaining protective immunity and that the out-
population of Treg but also TGF- production, secretion, and          come of infection hinges on the balance between Treg and
activation.                                                          effector T cell populations and potentially, the levels of TGF- .
   Creative pathogens such as obligate intracellular parasites          To more directly illuminate the involvement of TGF- in
can take advantage of a compromised host response and com-           regulation of infectious disease, the host response to the intra-
mandeer the host machinery to benefit their own survival and          cellular parasite L. major was monitored in TGF- 1 null and
growth. Able to survive and replicate within the hostile acid        wild-type littermates [111]. It is striking that in the absence of
environment of the phagolysosome of macrophages, leishmania          TGF- 1, mice were highly resistant to cutaneous infection of
parasites initially replicate and coexist with the host. Effective   the ear dermis, developing smaller lesions (if any) than the
resistance to leishmania infection is mediated by Th1 cells,         wild-type littermates with greatly diminished parasite num-
which through the production of IFN- , activate macrophages          bers. Invocation of an embellished defense in the absence of
to express elevated levels of iNOS and toxic NO, a molecule          TGF- 1 was attributed to an effective Th1 response with
with potent ability to kill intracellular parasites [99 –101]. The   constitutively elevated IFN- and iNOS, yielding high levels of
indispensable nature of iNOS in leishmania infections is most        NO and increased parasite-killing capacity. Additionally, ar-
evident in mice deficient in iNOS, which develop nonhealing,          ginase levels were dramatically reduced in the mutants as
disseminated lesions following infection with Leishmania major       compared with the susceptible wild-type mice, which at this
[102], coincident with reduced IFN- and increased TGF- in            early time-point, preferentially expressed high levels of argi-
the lesions and lymph nodes.                                         nase and diminished iNOS. TGF- has been shown to enhance
   TGF- , by its ability to suppress NO production [103],            arginase by diverting arginine use from iNOS to arginase,
inhibit TNF- and IFN- , and influence T cell differentiation          which effectively reduces NO levels and enhances production
[38], is instrumental in determining the outcome of leishmanial      of polyamines, which promote parasite growth and eventual

20   Journal of Leukocyte Biology Volume 76, July 2004                                                
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24     Journal of Leukocyte Biology Volume 76, July 2004                                                                         

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