Manifestations of cellmediated immunity in vitro

A number of model systems have been studied in vitro to evaluate the molecular mechanisms controlling T cell responses; these include proliferation, induction of cytolytic activity, expression of helper functions for antibody production, secretion of cytokines and biochemical signaling events. Clonal populations of T lymphocytes which retain normal pheno-typic characteristics and monoclonal antibodies reactive with different T cell surface structures have greatly facilitated the detailed analysis of these correlates of cell-mediated immunity in vitro. Monoclonal antibodies, which react with the TCRs, can serve as surrogate antigens, making it possible to distinguish the effects initiated by stimulation of the TCR from those involving other cell surface structures.

Many of the biological effects of T cells are mediated by secreted cytokines which affect the activities of different kinds of target cells. Different arrays of cytokines are produced by different T cell subsets following stimulation, and regulatory mechanisms that control which cytokines a particular T cell will secrete are beginning to be defined. It is clear that the array of cytokines secreted is of major functional significance. More than 15 different cytokines have been identified and their genes cloned. Their properties have been defined unequivocally, using products obtained by recombinant DNA technology. Most cytokines act on several different cell types.

Most if not all T lymphocyte proliferation is due to growth factors secreted by T cells. T lymphocytes stimulated with antigen are induced to express receptors for transferrin and for T cell growth factors, and they undergo cell division in response to cytokines having T cell growth factor activity. IL-2 was first identified on the basis of its ability to stimulate proliferation of T cells, and was thought initially to be the only T cell growth factor. Subsequently, however, IL-2 was found to stimulate proliferation of B cells as well. IL-4 is an additional T cell growth factor; it was first identified as a stimulatory factor for B cells. Both IL-2 and IL-4 serve as autocrine growth factors for the T cells which secrete them, and as paracrine growth factors for T cells which do not. IL-4 favors the development of cells that produce IL-4, IL-15, produced preferentially by nonlymphoid cells, also stimulates T cell growth. Uncontrolled growth of T cells that would occur through the autocrine pathway is prevented by regulatory processes which include desensitization of the T cell receptor for antigen, limitation of the period of time that cytokines are secreted, and modulation of the level of expression of growth factor receptors.

Much of the 'help' provided by T lymphocytes for antibody production is mediated by secreted cytokines. However, resting B cells require interactions with cell surface molecules expressed by T cells. The interaction of CD40, expressed constitutively by B cells, with CD40 ligand, expressed by T cells only upon activation, renders B cells responsive to IL-4 and other cytokines. This interaction stimulates the T cell as well. The most efficient help for B cells is provided by the T cell subset designated TH2, which secretes IL-4 and IL-5. These cytokines provide optimal B cell proliferation and differentiation. The TH1 subset, which secretes IL-2 and IFN-y but not IL-4 or IL-5, also may be able to provide help for B cells. Cytokines influence which antibody isotype is produced: IL-4 is required for immunoglobulin E (IgE) responses, and IFN-y and perhaps other factors from Tnl cells favor IgG2a production. In addition to their effects on antibody production by B cells, cytokines secreted by CD4+ helper T cells enhance generation of CD8+ cytolytic T cells. Thus, both T(I1 and Th2 cells appear to be able to serve as helper cells, although they may function in different situations and promote qualitatively different immune responses.

In addition to the antiviral effects that led to its designation, IFN-y causes increased expression of both class I and class II MHC antigens by macrophages and activation of macrophages for greater killing of ingested microorganisms. However, IFN-7 also inhibits the effects of IL-4 on B cells and inhibits proliferation of bone marrow cells induced by several other T cell cytokines. IL-6, which is secreted by some nonlymphoid cells, acts as a B cell stimulation and differentiation factor and stimulates the release of acute-phase reactants from liver cells; IL-3 stimulates pluripotential bone marrow stem cells and mast cells. IL-10 inhibits the ability of macrophages to stimulate TH1 cells. IL-12 increases production of IFN-7 by naive T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates granulocyte and monocyte precursors. Tumor necrosis factor a (TNF-a) is produced by macrophages as well as T cells; it causes leukocytosis, fever, weight loss and necrosis of some tumors. Lympho-toxin also kills target cells; its gene is closely linked to that for TNF-a, and there is 30% homology in the sequence of amino acids for these two proteins. Most major cytokines have probably been identified. These and other interactions among cytokines are important in the regulation of immune responses.

Although cytolytic activity has usually been associated with CD8+ T cells, many CD4+ T cells also have cytolytic potential. There are several distinct cytolytic mechanisms. Perforin, a complement-like molecule, is found in intracellular granules in cytolytic T cells and natural killer (NK) cells. Interaction between surface-bound Fas ligand, expresed by activated T cells, with Fas, expressed by some target cells, can also mediate cytotoxicity. Cytokines, such as lymphotoxin or TNF, can kill some target cells. The killing process is unidirectional, and the T cell is not injured by the cytolytic events. NK cells appear to use similar killing mechanisms as CD8+ cytolytic T cells. Most NK cells, at least in the human, appear not to be of the T cell lineage; the receptors that NK

cells use to interact with target cells have not been well characterized. Also, NK cells can mediate antibody-dependent cytotoxicity (ADCC); this involves interactions of Fc receptors on NK cells with antibody bound to target cells.

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