Clonal Expansion of T Cells

T cell proliferation in response to antigen recognition is mediated primarily by a combination of signals from the antigen receptor, costimulators, and autocrine growth factors, primarily IL-2. The cells that recognize antigen produce IL-2 and also preferentially respond to it, ensuring that the antigen-specific T cells are the ones that proliferate the most. The result of this proliferation is clonal expansion, which generates the large number of cells required to eliminate the antigen from a small pool of naive antigen-specific lymphocytes. Before antigen exposure, the frequency of naive T cells specific for any antigen is 1 in 105 to 106 lymphocytes. After microbial antigen exposure, the frequency of all CD8+ T cells specific for that microbe may increase to about 1 in 3 to 1 in 10, representing a >50,000-fold expansion of

Clonal

FIGURE 9-12 Clonal expansion of T cells. The numbers of CD4+ and CD8+ T cells specific for microbial antigens and the expansion and decline of the cells during immune responses are illustrated. The numbers are approximations based on studies of model microbial and other antigens in inbred mice.

Days after infection

FIGURE 9-12 Clonal expansion of T cells. The numbers of CD4+ and CD8+ T cells specific for microbial antigens and the expansion and decline of the cells during immune responses are illustrated. The numbers are approximations based on studies of model microbial and other antigens in inbred mice.

antigen-specific CD8+ T cells, and the number of specific CD4+ cells increases to 1 in 100 to about 1 in 1000 lymphocytes (Fig. 9-12). Studies in mice first showed this tremendous expansion of the antigen-specific population in some acute viral infections and, remarkably, it occurred within as little as 1 week after infection. Equally remarkable was the finding that during this massive antigen-specific clonal expansion, "bystander" T cells not specific for the virus did not proliferate. The expansion of T cells specific for Epstein-Barr virus and human immunodeficiency virus (HIV) in acutely infected humans is also on this order of magnitude. This conclusion has been reached by analyses of antigen-specific T cell responses in humans, using either fluorescent multimers of MHC molecules loaded with particular peptides or intracellular cytokine stains of T cells stimulated with peptides derived from these viruses (see Appendix IV).

Many of the progeny of the antigen-stimulated cells differentiate into effector cells. Because there are important differences in effector cells of the CD4+ and CD8+ lineages, these are described separately below. Effector cells are short-lived, and the numbers of antigen-specific T cells rapidly decline as the antigen is eliminated. After the immune response subsides, the surviving memory cells specific for the antigen number on the order of 1 in 104.

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