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The negative role exerted by cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) in the regulation of T-cell activity, as induced by T-cell receptor (TCR)/CD3 and CD28 costimulation, has been widely described. In the present work we investigated the role of CTLA-4 in the control of cell activation, as induced by costimulation of the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) in murine CD4+ T cells. Results show that CTLA-4 engagement inhibits interleukin-2 (IL-2) production, not only when induced by CD3/CD28 costimulation, but also when CD4+ T cells are costimulated by anti-CD3 and anti-LFA-1 monoclonal antibodies (mAbs). LFA-1 has been described to induce Ca2+ mobilization also in the absence of TCR engagement. Moreover, we found that CTLA-4 engagement negatively affects Ca2+ mobilization and NF-AT activation, as induced by LFA-1 engagement alone. PLCgamma1 phosphorylation was also dampened within minutes after CTLA-4 engagement. Altogether these data indicate that through the control of signals induced by different receptors, CTLA-4 could be a global attenuator of T-cell activation.

Although a large amount of information is available on the activity of CTLA-4 in T cells, the role of this receptor in B cells has not been previously characterized. Our results show that CD40 or LPS stimulation in the presence of IL-4 induces CTLA-4 expression in purified B cells; the maximum level is reached in both membrane and intracellular compartments after 48-72 h. Engagement of the B cell CTLA-4 by immobilized mAb inhibits IgG1 and IgE production and reduces the frequency of IgG1- and IgE-expressing B cells. Cepsilon and Cgamma(1) germline mRNA expression as well as NF-kappaB and STAT6 activation, events required for isotype switching, are also inhibited by CTLA-4 engagement. Together these findings show the critical role of CTLA-4 in the control of IL-4-driven isotype switching and suggest new approaches for modulating immediate-type hypersensitivity responses.