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					T Cell Effector Functions and Cell-mediated Immunity (Chapters 14 & 16)

Cell-mediated Immunity

•    mechanism for recognizing and eliminating cells infected by intracellular
     pathogens such as viruses or transformed into cancerous cells.
•    the cell-mediated arm of the immune response consists of antigen-specific CD4+
     T helper cells and CD8+ cytotoxic T lymphocytes (CTL); and nonMHC-restricted
     effector cells consisting of natural killer (NK) cells, NK-T cells, macrophages,
     neutrophils, and eosinophils.
•    involves 2 types of effector cells:
            1) Direct cytotoxic cells (CTL, NK-T cells, and NK cells).
            2) Th1 cells that mediate delayed-type hypersensitivity (DTH) responses.
•    the activity of specific and nonspecific components of cell-mediated immunity is
     dependent on cytokines made by T cells, NK cells, NK-T cells, and macrophages.

General properties of effector T cells (CD4+ Th1 and Th2 cells, CD8+ CTL)

•    in contrast to naive T cells, effector T cells do not require CD28-B7 costimulatory
     signals for activation following T cell receptor triggering. Instead, a costimulatory
     signal is provided by LFA-1 upon ligation by intracellular adhesion molecules
     (ICAMs) on target cells.
•    effector T cells express the CD45RO isoform that associates with the T cell
     receptor complex and CD4 or CD8 much better than the CD45RA isoform found
     on naive T cells.
•    effector T cells express substantially higher levels of CD2 and LFA-1 adhesion
     molecules in comparison to naive cells, which allows efficient binding of effector
     T cells to target cells.
•    effector T cells traffick to tertiary lymphoid tissues and sites of inflammation
     whereas naive T cells traffick to high endothelial venules in secondary lymphoid
     tissues.
•    unlike naive T cells, effector T cells express membrane-bound (eg., Fas ligand,
     CTL; TNF-β, Th1 cells; CD40 ligand, Th2 cells) and/or soluble (eg., cytotoxins,
     IFN-γ, TNF-β, CTL; type 1 cytokines, Th1 cells; type 2 cytokines, Th2 cells)
     effector molecules.

Antigen-specific CTL

•    are class I MHC-restricted CD8+ T cells that are capable of recognizing and
     eliminating virtually any altered cell in the body since almost all nucleated cells
     express MHC class I molecules.
•    CTL-mediated immune responses consist of an activation phase and an
     effector phase.

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Activation phase (Fig. 14-1)

•     effector CTL arise from naive CTL precursors activated via T cell receptor
      triggering by foreign antigen/class I MHC complexes, costimulation provided by
      CD28-B7 interactions, and IL-2 provided by Th1 cells.
•     upon activation, precursor CTL express high affinity IL-2 receptors that enable
      them to respond to IL-2 produced by proliferating Th1 cells. Activated precursor
      CTL also secrete IL-2 that in some cases is sufficient for autocrine
      growth/differentiation (Fig. 14-2).
•     CTL (like antigen-activated Th1 cells) are highly dependent on IL-2 for
      proliferation and differentiation into effector cells. IL-2 induces expression of
      genes coding for cytotoxins (perforin, granzymes) that are packaged in storage
      granules.
•     in the absence of IL-2 (levels of the cytokine fall after antigen is cleared from the
      body) both Th1 cells and CTL undergo apoptosis, providing a mechanism for
      rapidly terminating immune responses.

Effector phase (Fig. 14-6)

•     consists of conjugate formation, membrane attack, CTL-target cell
      dissociation, and target cell destruction.

•     conjugate formation between the CTL and target cell occurs within minutes and
      involves T cell receptor recognition of foreign peptide bound to class I MHC on
      the target cell. CD8 and LFA-1 stabilize the interaction. LFA-1 also provides a
      costimulatory signal. T cell receptor engagement by antigen causes a transient
      increase (persists for 5-10 minutes) in the avidity of LFA-1 for ICAMs on the
      target cell (Fig. 14-7, 14-8).
•     Golgi stacks and storage granules reorient in the cytoplasm and concentrate near
      the interface between the CTL and target cell.
•     during the membrane attack phase, the CTL exocytoses the cytocidal contents
      (perforin, granzymes) of storage granules into the space between the CTL and
      the target cell (Fig. 14-9). Perforin monomers, in the presence of calcium ions,
      undergo a change in conformation that allows them to insert into the target cell
      membrane and polymerize into pores. These pores allow granzymes to enter the
      target cell where they cleave intracellular substrates and trigger apoptosis.
      Alternatively, granzyme B binds to mannose-6-phosphate receptors on the target
      cells and the resulting complexes are internalized within vesicles. Perforin then
      allows granzyme B to be released from the vesicle into the cytoplasm.
•     CTL also kill target cells via the Fas ligand/Fas pathway in which the interaction
      of Fas ligand on CTL with Fas on target cells leads to apoptosis. This process is
      independent of calcium (even though calcium is always present in the

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      extracellular environment).
•     within minutes, CTL dissociate from the target cell and move on to form
      conjugates with other target cells. Fifteen minutes to 3 hours after dissociation
      the target cell is destroyed.

Target cell death by apoptosis (Fig. 14-11)

•     both the perforin/granzyme and Fas ligand/Fas cytotoxic pathways depend on
      the activation of caspases, which are cysteine proteases that cleave proteins
      after an aspartic acid residue.
•     both cytotoxic pathways ultimately result in the activation of caspase-3, which in
      turn leads to the activation of endonucleases that fragment nucleosomal DNA
      and additional proteases that disassemble the cytoskeleton of the target cell.
•     viral DNA is also fragmented during this process, thereby preventing viral
      replication during the interval before target cell destruction.

Natural killer (NK) cells

•     are nonspecific cytotoxic effector cells (5-10% of recirculating lymphocytes) that
      play an important role in defending the body against viruses and some cancers.
      NK cells are the first line of defense against viral infection because of their rapid
      activation by IFNs and IL-12 (Fig. 14-12).
•     recognition of target cells by NK cells is not MHC restricted and NK cells do not
      exhibit immunologic memory.
•     are an important source of cytokines such as IFN-γ that promotes Th1
      differentiation and inhibits Th2 development. IFN-γ production by NK cells is
      induced by IL-12 from macrophages and dendritic cells.
•     are derived from the same progenitor cells as T cells but NK cells do not develop
      exclusively in the thymus. NK cells express IL-2 receptor β chains and CD16 but
      do not express the T cell receptor or CD8.

Mechanism of NK cell-mediated cytotoxicity

•     the cytotoxic process is similar to CTL-mediated cytolysis. However, unlike CTL,
      NK cells are constitutively active since they have cytoplasmic granules containing
      perforin and granzymes and also express Fas ligand prior to encountering target
      cells.
•     NK cells use 2 different types of receptors to distinguish altered self-cells from
      normal self cells (Fig. 14-14). One category of receptor delivers an activating
      signal while the other category of receptor delivers an inhibitory signal. The
      balance between activating and inhibitory signals determines whether or not an
      NK cell will ultimately kill the target cell. This is known as the opposing-signals
      model.

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•     although activating receptors are still being identified, C-type lectins that
      recognize altered carbohydrate structures on virus-infected or transformed target
      cells are an important category of activating receptor. CD2 and CD16 (in the
      context of antibody-dependent cel-mediated cytotoxicity or ADCC) are also
      important activating receptors.
•     inhibitory receptors consist of C-type lectin inhibitory receptors and killer cell
      inhibitory receptors, both of which deliver an inhibitory signal following
      interaction with class I MHC molecules. As a result, there is an inverse correlation
      between MHC class I expression and target cell susceptibility to killing by NK
      cells, i.e., cells which express low levels of MHC class I molecules are killed by
      NK cells while cells with normal levels of MHC class I molecules are spared.
•     Inhibitory signals always override activation signals, preventing cytotoxicity,
      cytokine synthesis, and NK cell proliferation.

NK-T cells (note that this important cell subset is only briefly mentioned in the text)

•     NK-T cells are a small subset of T cells that also express NK cell markers such as
      NK1.1.
•     May be double-negative or CD8+; T cell receptor α chains are very limited in
      diversity.
•     T cell receptors interact with a class I MHC-like nonpolymorphic molecule called
      CD1, which is present on antigen presenting cells and epithelial cells and
      presents lipid antigens.
•     Upon triggering, NK-T cells secrete large amounts of cytokines that support
      antibody formation (IL-4), as well as inflammation and the expansion of cytotoxic
      T cells (IFN-γ). NK-T cells also have NK cell-like cytotoxic activity.
•     NK-T cells are considered to be a rapid response system to provide early help
      while conventional T helper cell development is still taking place, as well as
      guiding development of the immune response (humoral or cellular) that is most
      appropriate for the infection.


Antibody-dependent cell-mediated cytotoxicity (ADCC) (Fig. 14-15)

•     NK cells, neutrophils, eosinophils, monocytes, and macrophages express
      receptors for the Fc region of IgG (eg., CD16 on NK cells). This allows these cell
      types to mediate ADCC reactions in which nonspecific killer cells are directed to
      target cells by IgG bound to target cell surface molecules.
•     Neutrophils, eosinophils and macrophages that are activated through their Fc
      receptors become more metabolically active and release the lytic contents of
      their cytoplasmic lysosomes. NK cells that are activated through CD16 exocytose
      the contents of their cytoplasmic granules (granzymes and perforin) and kill by
      the Fas ligand/Fas pathway. Activated NK cells, monocytes, and macrophages

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     also secrete TNFα.

The delayed-type hypersensitivity (DTH) response

•    a localized inflammatory reaction induced by cytokines secreted by Th1 cells and
     characterized by a large influx of nonspecific inflammatory cells, especially
     macrophages. The DTH response is protective against intracellular bacteria,
     fungi, protozoans and some viruses. In some cases DTH responses cause
     extensive tissue damage that itself contributes to disease.

Phases of a DTH response (Fig. 16-17)

     1) Sensitization phase - antigen presenting cells (macrophages, dendritic cells)
     pick up antigen and transport antigen to regional lymph nodes where it is
     presented to T helper cells that become activated, undergo clonal expansion, and
     differentiate into Th1 cells. In humans vascular endothelial cells can function as
     antigen presenting cells for the development of DTH responses. Sensitization
     takes 1-2 weeks following first contact with antigen.

     2) Effector phase - in response to a subseqent exposure to the antigen
     (presented in the context of self class II MHC by antigen presenting cells such as
     tissue macrophages, dendritic cells or vascular endothelial cells), memory Th1
     cells are activated and secrete cytokines that recruit and activate macrophages,
     as well as other nonspecific inflammatory cells. The response takes 24 hours to
     develop and peaks within 48 to 72 hours. The macrophage is the main effector
     cell (makes up 80-90% of infiltrating cells) of the DTH response. Activated
     macrophages have increased phagocytic activity and an increased ability to kill
     phagocytosed and intracellular microorganisms, thereby providing an effective
     defense against intracellular bacteria and parasites. Activated macrophages also
     increase expression of MHC class II and adhesion molecules, resulting in more
     effective antigen presentation to T helper cells. However, a prolonged DTH
     response may lead to extensive host tissue damage and granuloma formation
     (Fig. 16-18).

Cytokines involved in DTH responses

•    IL-3 and GM-CSF induce localized hematopoiesis of monocytes and neutrophils.
•    IL-2 supports the autocrine growth of antigen-activated Th1 cells.
•    TNF-ß, IFN-γ (from Th1 cells ), TNF-α and IL-1 (from macrophages) stimulate
     the extravasation of circulating neutrophils and monocytes (which differentiate
     into macrophages) from blood vessels by increasing adhesion molecule
     expression and altering the shape of vascular endothelial cells.
•    Monocyte chemotactic and activating factor (MCAF) attracts tissue

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macrophages to the DTH site. IFN-γ activates tissue macrophages leading to
increased killing and expression of class II MHC molecules. Migration-
inhibition factor (MIF) is a chemokine that prevents macrophages from
migrating away from the DTH site. IFNγ and TNFß attract macrophages.




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