TCR/self-antigen interactions drive double-negative T cell peripheral expansion and differentiation into suppressor cells

Mature CD4(-)CD8(-) alpha beta (+) T cells (DNTC) in the periphery of TCR t ransgenic mice are resistant to clonal deletion in cognate Ag-expressing (A g+) mice. Previously, we have characterized DNTC populations bearing the al loreactive 2C TCR in Ag-free (Ag-) and Ag+ mice. Despite appearing function ally anergic when challenged with cognate Ag in vitro, Ag-experienced DNTC exhibit markers of activation/memory, a lowered threshold of activation, ex vivo cytolytic activity, and the ability to rapidly secrete IFN-gamma. Rem arkably, these memory-like DNTC also possess potent immunoregulatory proper ties, competing effectively for bystander-produced IL-2 and suppressing aut oreactive CD8(+) T cell proliferation via a Fas/FasL-dependent cytolytic me chanism. The fact that DNTC recovered from Ag+ mice possess markers and att ributes characteristic of naive CD8(+) T cells that have undergone homeosta sis-induced proliferation suggested that they may be derived from a similar peripheral expansion process. Naive DNTC adoptively transferred into Ag-be aring hosts rapidly acquire markers and functional attributes of DNTC that have continually developed in the presence of Ag. Thus, the peripheral sele ction and maintenance of such autoreactive cells may serve to negatively re gulate potential autoimmune T cell responses.