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David F. Touqh, Persephone Borrow, Jonathan Sprent*
T cell proliferation in vivo is presumed to reflect a T cell receptor (TCR)mediated polyclonal response directed to various environmental antigens. However, the massive proliferation of T cells seen in viral infections is suggestive of a bystander reaction driven by cytokines instead of the TCR. In mice, T cell proliferation in viral infections preferentially affected the CD44^sup hi^ subset of CDS+ cells and was mimicked by injection of polyinosinic-polycytidylic acid [poly(l:C)], an inducer of type I interferon (IFN I), and also by purified IFN I; such proliferation was not associated with up-regulation of CD69 or CD25 expression, which implies that TCR signaling was not involved. IFN I [poly(l:C)]stimulated CD8+ cells survived for prolonged periods in vivo and displayed the same phenotype as did long-lived antigen-specific CD8+ cells. IFN I also potentiated the clonal expansion and survival of CD8+ cells responding to specific antigen. Production of IFN I may thus play an important role in the generation and maintenance of specific memory.
Viral infections generally induce vigorous immune responses that culminate in a longlasting state of immune memory. The sharp transient increase in total T cell numbers found in certain viral infections and the activation of specific T cells by heterologous viruses suggest that a substantial component of the T cell proliferative response is not antigen-specific (1). T cell proliferation in viral infections has not been quantitated, although the number of cycling CD8+ cells in mice with influenza infection greatly exceeds the number of virus-specific cells (2). To quantitate T cell proliferation, the DNA precursor bromodeoxyuridine (BrdU) was given to mice to label T cells during infection with lymphocytic choriomeningitis virus (LCMV).
Administration of BrdU in the drinking water to uninfected (control) adult thymectomized (AT x) C57BL/6 (B6) mice led to slow and progressive BrdU labeling of CD4+ and CD8+ cells in the spleen (3) and in pooled lymph nodes (LNs) (Fig. 1, A and B) (4). Labeling occurred more rapidly for "memory-phenotype" CD44^ sup hi^ cells (20 to 25% of T cells) than for "naive-phenotype" CD44^ sup hi^ cells (Fig. 1, C through F). The rate and extent of BrdU labeling of T cells increased after infection with LCMV and was most conspicuous for the CD44^sup hi ^...