Clonal anergy in self‐reactive α/β T cells is abrogated by heat‐shock protein‐reactive γ/δ 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 α/β and γ/δ 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‐2^d, Mls‐1^b2^a, I‐E⁺, 7–8 month old) nude mice. Consistent with recent reports, T cells bearing V_β3 or V_β11, which are important for recognizing proteins encoded by the Mls‐2^a or the I‐E allele, respectively, are readily detected in age nude mice. The V_β3‐ or V_β11‐bearing T cells, however, do not proliferate in response to staphylococcal enterotoxin A which specifically stimulates V_β3‐ or V_β11‐bearing T cells. When exogenous recombinant interleukin 2 was added to the culture, the V_β3‐bearing T cells in aged nude mice significantly proliferated in response to staphylococcal enterotoxin A. Aged nude mice also contained a substantial level of γ/δ T cells which account for 15.6% of all Thy‐1.2⁺ cells. The γ/δ 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.