LFA-1 overexpression and T cell autoreactivity: mechanisms.
Overexpressing LFA-1 (CD11a/CD18) on antigen specific CD4+ T cells makes the cells proliferate to normally subthreshold stimuli, including self-Ia molecules without specific antigen. The mechanisms by which this occurs are unknown, but potentially include transmission of an increased costimulatory signal, overstabilization of normally low affinity TCR-Ia interactions, or both. A role for increased costimulatory signaling was tested by culturing control and CD18-transfected antigen-specific T cells clones with anti-CD3 and anti-CD11a. Minimal calcium fluxes were detected, but increased protein tyrosine phosphorylation was observed in the transfectants. However, the proliferative response to graded amounts of these antibodies were identical in the transfectants and controls, suggesting that increased signaling alone was insufficient to cause the increased responsiveness. To test for overstabilization, transfected and control clones were cultured with syngeneic Mø with or without antigen. The transfected but not control cells downregulated TCR expression in response to Mø alone, thus demonstrating successful TCR signaling to a low affinity interaction. These results indicate that LFA-1 overexpression permits TCR signal transmission to a normally subthreshold stimulus presented by Mø, consistent with overstabilization. LFA-1 overexpression also causes increased tyrosine phosphorylation, but this alone is not sufficient to cause a proliferative response to low level stimuli.
Kaplan
M J
MJ
Dept. of Medicine, University of Michigan, Ann Arbor 48109, USA.
Beretta
L
L
Yung
R L
RL
Richardson
B C
BC
D000818:Animals; D000941:Antigens / Q000276:immunology; D018821:CD18 Antigens / Q000096:biosynthesis* / Q000235:genetics; D020013:Calcium Signaling; D002455:Cell Division; D003207:Conalbumin / Q000276:immunology; D003432:Cross-Linking Reagents; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008806:Mice, Inbred AKR; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D000941:Antigens; D018821:CD18 Antigens; D003432:Cross-Linking Reagents; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D003207:Conalbumin