Clonal anergy in self-reactive alpha/beta T cells is abrogated by heat-shock protein-reactive gamma/delta T cells in aged athymic nude mice.

Although T cells proliferate and differentiate primarily in the thymus, athymic nude mice contain an appreciable level of T cell receptor alpha/beta and gamma/delta T cells, suggesting the existence of the extrathymic pathway in the development of both T cells. Recent studies with nude mice indicate that clonal deletion of self-reactive T cells does not occur extrathymically. In the present study, we have investigated the responsiveness of self-reactive T cells differentiating along an extrathymic pathway in aged BALB/c (H-2d, Mls-1b2a, I-E+, 7-8 month old) nude mice. Consistent with recent reports, T cells bearing V beta 3 or V beta 11, which are important for recognizing proteins encoded by the Mls-2a or the I-E allele, respectively, are readily detected in age nude mice. The V beta 3- or V beta 11-bearing T cells, however, do not proliferate in response to staphylococcal enterotoxin A which specifically stimulates V beta 3- or V beta 11-bearing T cells. When exogenous recombinant interleukin 2 was added to the culture, the V beta 3-bearing T cells in aged nude mice significantly proliferated in response to staphylococcal enterotoxin A. Aged nude mice also contained a substantial level of gamma/delta T cells which account for 15.6% of all Thy-1.2+ cells. The gamma/delta T cells proliferated and produced a significant level of interleukin 2 in response to the 65-kDa mycobacterial heat-shock protein, which is highly homologous to its eukaryotic counterpart. These results suggest that unresponsiveness of self-reactive T cells may be reversed by T cells responding to stress proteins expressed by the invading microbes and/or the stressed autologous cells.