Anergy in CD4 memory T lymphocytes. II. Abrogation of TCR-induced formation of membrane signaling complexes.
Memory and naive CD4 T cells have unique regulatory pathways for self/non-self discrimination. A memory cell specific regulatory pathway was revealed using superantigens to trigger the TCR. Upon stimulation by bacterial superantigens, like staphylococcal enterotoxin B (SEB), TCR proximal signaling is impaired leading to clonal tolerance (anergy). In the present report, we show that memory cell anergy results from the sequestration of the protein tyrosine kinase ZAP-70 away from the TCR/CD3ζ chain. During SEB-induced signaling, ZAP-70 is excluded from both detergent-resistant membrane microdomains and the immunological synapse, thus blocking downstream signaling. We also show that the mechanism underlying memory cell anergy must involve Fyn kinase, given that the suppression of Fyn activity restores the movement of ZAP-70 to the immunological synapse, TCR proximal signaling, and cell proliferation. Thus, toleragens, including microbial toxins, may modulate memory responses by targeting the organizational structure of memory cell signaling complexes.
The Department of Biomedical Sciences, The School of Public Health, The University at Albany, Albany, New York 12201-0509, United States. William.Lee@wadsworth.org
William T
WT
Lee
Aparna
A
Prasad
Andrew R O
AR
Watson
D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D004768:Enterotoxins / Q000276:immunology; D007156:Immunologic Memory; D051379:Mice; D018345:Mice, Knockout; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013210:Staphylococcus / Q000276:immunology
D004768:Enterotoxins; D011948:Receptors, Antigen, T-Cell; C031818:enterotoxin B, staphylococcal; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn