Multiple cytokine interactions regulate Ly-6E antigen expression: cooperative Ly-6E induction by IFNs, TNF, and IL-1 in a T cell lymphoma and in its induction-deficient variants.
The cell surface Ly-6E antigen, known to play a role in T cell activation, is up-regulated by IFNs. In the present study, we investigated the possible interactions between IFNs and other cytokines in this regulation. As a model system, we used the YAC T cell lymphoma, in which Ly-6E is normally absent but can be highly induced both at the mRNA and surface protein levels by IFN-gamma or IFN-alpha/beta. The combination of the two IFNs was found to result in markedly synergistic Ly-6E induction in this cell line. Moreover, mutants of YAC cells were isolated that did not respond to the Ly-6E-inducing action of IFN-gamma or IFN-alpha/beta alone but did respond to their combination. Such a synergistic interaction is consistent with the notion that the two IFN types utilize different intracellular mechanisms to induce Ly-6E expression. Ly-6E induction mediated by IFN-gamma or IFN-alpha/beta was also enhanced by cotreatment with TNF-alpha or IL-1 alpha, which by themselves had no detectable Ly-6E-inducing effect. These two cytokines similarly synergized with IFNs to trigger a response in several Ly-6E-induction-deficient mutants. However, their action could be dissociated in one mutant (B54) where the response to IFN-alpha/beta was enhanced by TNF-alpha, but not by IL-1 alpha. Altogether, these data indicate that Ly-6E antigen expression is regulated by the interaction of several inflammatory cytokines, which may provide a mechanism for the local modulation of T cell activation. The YAC cell mutants described here should facilitate further analysis of the molecular bases of Ly-6E regulation.
Altmeyer
A
A
Department of Immunology, Merck, Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Staruch
M J
MJ
Cofano
F
F
Landolfo
S
S
Dumont
F J
FJ
D000950:Antigens, Ly / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D016399:Lymphoma, T-Cell / Q000276:immunology*; D009154:Mutation; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000950:Antigens, Ly; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons; D000242:Cyclic AMP