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

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Abstract
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‐2d, Mls‐1b2a, I‐E+, 7–8 month old) nude mice. Consistent with recent reports, T cells bearing Vβ3 or Vβ11, 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 Vβ3‐ or Vβ11‐bearing T cells, however, do not proliferate in response to staphylococcal enterotoxin A which specifically stimulates Vβ3‐ or Vβ11‐bearing T cells. When exogenous recombinant interleukin 2 was added to the culture, the Vβ3‐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.