CTL induction and growth

Most MHC-restricted CTL responses directed to viral antigens, tumor antigens, soluble protein and minor histocompatibility antigens require in vivo immunization or priming. In the case of strong responses, MHC-restricted, antigen-specific T cells can be obtained by day 7 postimmunization. Upon in vitro secondary restimulation with limiting numbers of primed precursors one can obtain clonal CTL populations. In general, class I MHC-restricted CTLs require an exogenous source of T cell growth factor, interleukin 2 (IL-2), in addition to the antigenic stimulus, while class II MHC-restricted CTLs do not. If cloned in the absence of exogenous IL-2 and at a high precursor density per well, rare CD8+, class I MHC-restricted CTLs which produce IL-2 can be selected. CTL antigen specificity and MHC restriction can also be determined in proliferation assays. At one time, cytotoxic T cell effectors were considered to be end-stage cells incapable of proliferating (much like antibody-secreting plasma cells). It has been shown, however, that CTLs can continue to proliferate but only upon specific antigenic stimulation. Some general features of CTL induction are depicted in Figure 1. The events are the same for both class I MHC-restricted CD8+ CTLs and class II MHC-restricted CD4+ CTLs. The first signal in the activation of precursor CTL (pCTL) is the antigen/MHC complex recognized by the pCTL T

cell receptor (TCR). The costimulatory (or second) signal once considered to be IL-1 (soluble or mem-brane-bound) for CD4+ pCTL, is now thought to be B7(CD80), the ligand for CD28 expressed on the pCTL. The activated T cells undergo RNA synthesis, protein synthesis and expression of IL-2 receptor a (IL-2Ra) resulting in expression of high-affinity IL-2 rcceptors (IL-2Ra(3y). Upon engagement of IL-2 by IL-2R the T cell blasts undergo DNA synthesis and subsequent cell division. Whether an additional cytotoxic differentiation factor (CDF), such as IL-12, is required at this time to allow the T cells to gain cytolytic effector function remains to be demonstrated. Whether mature CTLs and memory CTLs are one and the same also is not known. These mature/memory CTL eventually downregulate IL-2Ra expression and stop proliferating until they receive an antigenic stimulus once again.

Also depicted in Figure 1 the current scheme that there are two predominant pathways of antigen presentation, one for class 1 MHC-restricted recognition and the other for class II MHC-restricted recognition. Crossover between the two pathways have been described to occur. For the most part, however, antigen synthesized endogenously within the antigen-presenting cell or target cell (or somehow introduced into the cell cytoplasm) can be processed and presented in the context of class I MHC molecules. Antigens which are taken up by an endocytic route by the antigen-presenting cell or target cell are processed and presented in the context of class II MHC molecules. As a result of this distinction, infectious virus can elicit both class I and class II MHC-restricted CTLs in vivo while inactivated virions generally elicit just class II MHC-restricted T cells in vivo.

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