Peripheral tolerance in transgenic mice expressing class I MHC L(d) only on cardiac cells

The fate of autoreactive T cells exposed to extrathymic self-antigen is examined in a double transgenic (DTG) mouse [(L(d+) cardiacx2C)F1], where cardiac myocytes alone express L(d) and T cells express an antigen receptor (2C TCR) against L(d).

Naïve cardiac L(d+) single transgenic (STG) mice (before breeding with 2C) and DTG mice were examined for evidence of autoimmunity. The L(d+) STG hearts were then transplanted to syngeneic L(d-) wild type C57BL/6 to evaluate the heart's immunogenicity. L(d+) skin grafts were transplanted to non-transgenic B6, transgenic 2C, STG, and DTG mice. Phenotype analysis of peripheral 1B2+(identifies 2C T cells), CD4+, and CD8+ T cells was performed by FACS. In vitro MLC and CTL, with and without the addition of IL-2 and suppressor cell assays, were evaluated.

Neither STG nor DTG hearts developed any evidence of autoimmunity by histology. In contrast, B6 mice rejected the L(d+) STG heart in 17+/-9.7 days (P<0.01), while a syngeneic B6 heart transplant was accepted indefinitely. Survival of L(d+) skin grafts was prolonged in both STG and DTG mice. FACS quantitation revealed that while there was no deletion of peripheral 2C cells in the DTG, these 2C T cells did have a significantly reduced proliferative and cytotoxic response to H-2L(d). Restoration of the proliferative and cytotoxic response of the DTG cells by the addition of IL-2 was consistent with a state of anergy.

These findings suggest that the expression of extrathymic class I MHC expression alone did not trigger autoimmune reactions but that the T cells can be rendered anergic to the specific 'self' antigen.