Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules

In the thymus, T cells are selected according to their T cell receptor (TCR) specificity. After positive selection, mature cells are exported from primary lymphoid organs to seed the secondary lymphoid tissue. An important question is whether survival of mature T cells is an intrinsic property or requires continuous survival signals, i.e., engagement of the TCP by major histocompatibility complex (MHC) molecules in the periphery, perhaps in a similar way as occurring during thymic positive selection. To address this issue we used recombination-activating gene (Rag)-deficient H-2(b) mice expressing a transgenic TCR restricted by I-Ed class II MHC molecules. After engraftment with Rag(-/-) H-2(d) fetal thymi, CD4(+)8(-) peripheral T cells emerged. These cells were isolated and transferred into immunodeficient hosts of H-2(b) or H-2(d) haplotype, some of the latter being common cytokine receptor gamma chain deficient to exclude rejection of H-2(b) donor cells by host natural killer cells. Our results show that in the absence, but not in the presence, of selecting MHC molecules, peripheral mature T cells are short lived and disappear within 7 wk, indicating that continuous contact of the TCR with selecting MHC molecules is required for survival of T cells.