Uncoupling of cytokine mRNA expression and protein secretion during the induction phase of T cell anergy.
The CD4+ T cell clone HA1.7 may be made specifically nonresponsive, or anergic, to its cognate Ag, an influenza hemagglutinin peptide (HA), by pretreatment with the superantigen Staphylococcus aureus enterotoxin B or with high concentrations of HA itself. We compare the patterns of mRNA expression and protein production of selected T cell cytokines during the first 24 h after treatments that induce anergy in HA1.7 and during the same period after treatments that simulate normal cellular activation. The cytokines examined include TNF-alpha, IL-8/neutrophil activating protein-1 and the RANTES/SIS cytokines, a family of small secreted proteins with inflammatory and potential antiproliferative and leukocyte regulating activities. Messenger RNA for TNF-alpha, human MIP-1 alpha, human MIP-1 beta, and IL-8 are all induced during the development of clonal anergy in HA1.7, and these levels are significantly higher than those seen during activation of the clone using an anti-CD3 antibody and IL-2. These high levels of mRNA also persist longer than those seen after anti-CD3 and IL-2 activation. However, the increased levels of mRNA are not typically accompanied by increased protein secretion. In all cases but one, the amount of cytokine secreted by HA1.7 cells was greater after anti-CD3 and IL-2 treatments than after anergy-inducing treatments. Thus, the induction of T cell anergy in HA1.7 does not appear to require a general inhibition of T cell cytokine mRNA expression, and, in fact, anergy treatments appear to superinduce certain cytokine transcripts, but anergy-specific posttranscriptional mechanisms may exist by which cytokine release is regulated.
Schall
T J
TJ
Genentech Incorporated, South San Francisco, CA 94080.
O'Hehir
R E
RE
Goeddel
D V
DV
Lamb
J R
JR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D017252:CD3 Complex; D054407:Chemokine CCL4; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D007108:Immune Tolerance; D016209:Interleukin-8 / Q000235:genetics; D019402:Macrophage Inflammatory Proteins; D015846:Monokines / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D054407:Chemokine CCL4; D016207:Cytokines; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha