Defective T cell receptor-mediated signal transduction in memory CD4 T lymphocytes exposed to superantigen or anti-T cell receptor antibodies.
Lymphocytes must promote protective immune responses while still maintaining self-tolerance. Stimulation through the T cell receptor (TCR) can lead to distinct responses in naive and memory CD4 T cells. Whereas peptide antigen stimulates both naive and memory T cells, soluble anti-CD3 antibodies and bacterial superantigens stimulate only naive T cells to proliferate and secrete cytokines. Further, superantigens, like staphylococcal enterotoxin B (SEB), cause memory T cells to become anergic while soluble anti-CD3 does not. In the present report, we show that signal transduction through the TCR is impaired in memory cells exposed to either anti-CD3 or SEB. A block in signaling leads to impaired activation of the kinase ZAP-70 so that downstream signals and cell proliferation do not occur. We further show that the signaling defect is unique to each agent. In anti-CD3-treated memory T cells, the src kinase Lck is only transiently activated and does not phosphorylate and activate ZAP-70. In SEB-treated memory T cells, ZAP-70 does not interact with the TCR/CD3 complex to become accessible to Lck. Finally, we provide evidence that alternative signaling pathways are initiated in SEB-treated memory cells. Altered signaling, indicated by an elevation in activity of the src kinase Fyn, may be responsible for memory cell anergy caused by SEB. Thus, differentiation of naive T cells into memory cells is accompanied by alterations in TCR-mediated signaling that can promote heightened recall immunity or specific tolerance.
Watson
Andrew R O
AR
The Department of Biomedical Sciences, The School of Public Health, The University at Albany, Albany, NY 12201-0509, USA.
Lee
William T
WT
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D004768:Enterotoxins / Q000276:immunology; D004789:Enzyme Activation; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019000:Phosphotyrosine / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004768:Enterotoxins; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D019000:Phosphotyrosine; C031818:enterotoxin B, staphylococcal; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase