The developmental requirements for immunological memory, a central feature of adaptive immune responses, is largely obscure. We show that as naive CD8 T cells undergo homeostasis-driven proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon γ faster upon restimulation. Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28. These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.
To determine how murine memory and naive T cells differ, we generated large numbers of long-lived memory CD8؉ T cells and compared them to naive cells expressing the same antigen-specific receptor (T cell receptor; TCR). Although both populations expressed similar levels of TCR and CD8, on antigen stimulation in vitro memory T cells down-regulated their TCR faster and more extensively and secreted IFN-␥ and IL-2 faster than naive T cells. Memory cells were also larger, and when freshly isolated from mice they contained perforin and killed target cells without having to be restimulated. They further differed from naive cells in requiring IL-15 for proliferation and in having a greater tendency to undergo apoptosis in vitro. On antigen stimulation in vivo, however, they proliferated more rapidly than naive cells. These findings suggest that, unlike naive T cells, CD8 memory T cells are intrinsically programmed to rapidly express their effector functions in vivo without having to undergo clonal expansion and differentiation.Following an initial response to antigen, some lymphocytes acquire altered properties and persist for prolonged periods. The collective behavior of these cells, termed immunologic memory, constitutes one of the cardinal features of the vertebrate adaptive immune system (reviewed in refs. 1-3). For B lymphocytes the distinguishing properties between the cells responsible for memory (memory B cells) and their precursors (naive B cells) have long been known (4, 5). In response to antigenic stimulation, memory B cells secrete high-affinity IgG (or IgE or IgA) rather than the low-affinity Abs (IgM and IgG) produced during the primary B cell response (6). These differences result from Ig gene class switching, somatic hypermutation of Ig variable gene segments, and selection of B cells expressing high-affinity Ig receptors by antigen during the primary response to antigen (7-9). The antigen-stimulated generation of memory B cells is largely responsible for the effectiveness of natural infection and vaccines in conferring immunity against many microbial pathogens.Although memory T cells are known to exist (10-20), the properties that distinguish them from their naive precursors are only known to a limited extent. A major obstacle preventing a more complete characterization of memory T cells has been their limited availability and the heterogeneity of the memory T cells expressing different T cell receptors (TCRs) in most model systems. In this study we modified an adoptive transfer protocol (21) by using recombination activating gene-1 (RAG1)-deficient mice as transfer recipients. Because they lack endogenous lymphocytes, a substantial number of memory T cells (3-4 ϫ 10 6 ͞mouse) were generated after adoptive transfer of CD8 TCR transgenic T cells followed by immunization with antigenic peptide. Functional comparisons of the resulting CD8 memory T cells with their naive counterparts revealed some unique properties that may underlie the characteristic memory T cell response. ) mice, backcrossed t...
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