Homeostatic T Cell Proliferation

Through positive and negative selection, the thymus allows a small fraction of immature CD4 ϩ 8 ϩ double positive thymocytes to differentiate into mature CD4 ϩ 8 Ϫ or CD4 Ϫ 8 ϩ single positive cells; these cells are released into the periphery to establish the mature T cell pool. Positive selection rescues thymocytes that express TCR with low affinity for peptides bound to MHC molecules expressed on corti-cal epithelial cells. Conversely, negative selection eliminates thymocytes with high affinity for MHC–peptide complexes , thereby leading to self-tolerance induction (1, 2). Via this process of selection, the thymus generates a peripheral repertoire that is largely depleted of overtly autoreactive T cells but retains low but significant reactivity for self-MHC molecules. Retaining weak affinity for self-MHC/ peptide ligands has generally been considered a requirement for T cells to optimally recognize foreign antigens in the context of self-MHC molecules. However, recent findings strongly suggest that low-level self-reactivity serves an additional purpose: namely, to maintain survival and homeosta-sis of naive T cells (for a review, see reference 3). Mature naive T cells are usually considered to remain in a dormant state unless awakened by foreign antigens expressed on activated APCs. This view has now been modified by the finding that prolonged survival of naive T cells in a resting state requires low-level TCR signaling from contact with self-MHC/peptide ligands (i.e., with MHC class I molecules for CD8 ϩ cells and class II molecules for CD4 ϩ cells [4–10]). In the absence of these self-ligands, naive T cells gradually disappear. Evidence for active signal-ing through the TCR is also provided by the finding that survival of resting naive T cells requires expression of lung Kruppel-like factor (LKLF), a member of Kruppel-like zinc transcription factor family (11). This molecule is presumably involved in translating covert TCR signaling into cell survival cues. It has long been known that mature T cells are regulated at a population level by homeostatic mechanisms that maintain the total size of the T cell pool at a near-constant level (12–14). Normally, expansion of the T cell pool during an immune response is followed by a deletion phase in which most of the newly generated effector cells are eliminated at the end of the response, thereby restoring total T cells numbers to normal levels (15, 16). On the other hand, it is also well established that T cells have the capacity to spontaneously …