LFA-1 overexpression and T cell autoreactivity: Mechanisms

Overexpressing LFA-1 (CD11a/CD18) on antigen specific CD4+ T cells makes th e cells proliferate to normally subthreshold stimuli, including self-Ia mol ecules without specific antigen. The mechanisms by which this occurs are un known, but potentially include transmission of an increased costimulatory s ignal, overstabilization of normally low affinity TCR-Ia interactions, or b oth. A role for increased costimulatory signaling was tested by culturing c ontrol and CD18-transfected antigen-specific T cells clones with anti-CD3 a nd anti-CD11a. Minimal calcium fluxes were detected, but increased protein tyrosine phosphorylation was observed in the transfectants. However, the pr oliferative response to graded amounts of these antibodies were identical i n the transfectants and controls, suggesting that increased signaling alone was insufficient to cause the increased responsiveness. To test for overst abilization, transfected and control clones were cultured with syngeneic Mo with or without antigen. The transfected but not control cells downregulat ed TCR expression in response to MB alone, thus demonstrating successful TC R signaling to a low affinity interaction. These results indicate that LFA- 1 overexpression permits TCR signal transmission to a normally subthreshold stimulus presented by MB, consistent with overstabilization. LFA-1 overexp ression also causes increased tyrosine phosphorylation, but this alone is n ot sufficient to cause a proliferative response to low level stimuli.