Multiple cytokines sharing the common receptor gamma chain can induce CD154/CD40 ligand expression by human CD4+ T lymphocytes via a cyclosporin A-resistant pathway.
Expression of CD154/CD40 ligand (CD154/CD40L), an important molecular component of CD4+ T-cell help, can be triggered by T-cell receptor (TCR) stimulation. Dephosphorylation of the transcriptional element Nuclear Factor of Activated T cells-1 (NFAT1) is a critical activation step in the TCR-initiated signal transduction cascade which promotes CD154/CD40L expression. Cyclosporin A (CsA), which interferes with NFAT1 activation, has been shown to be an effective inhibitor of TCR-triggered CD154/CD40L expression by resting T cells. We now report that recombinant interleukin-2 (rIL-2) is also capable of inducing CD154/CD40L on CD4+ T lymphoblasts via a pathway triggered independently of the CD3/TCR receptor complex. Recombinant IL-2-mediated CD154/CD40L expression, in contrast to that triggered by CD3/TCR stimulation, is only partially inhibited by CsA. The capacity of rIL-2 to induce CD154/CD40L expression by T lymphoblasts also extends to a restricted number of cytokines sharing the cytokine receptor common gamma chain, including IL-15, and, to a lesser extent, IL-7, but not IL-4. A similar CsA-resistant CD154/CD40L induction pathway can be triggered in primary T cells by the combination of anti-CD3 stimulation and recombinant lymphokines. In contrast to T lymphoblasts, the CsA-resistant CD154/CD40L induction in primary lymphocytes can be efficiently triggered by multiple cytokines which bind the common gamma chain receptor family. The data outline a novel pathway of CD154/CD40L induction which is, at least in part, independent of NFAT1 and resistant to CsA. A more complete understanding of the mechanisms governing CD154/CD40L expression may facilitate the rational design of specifically targeted immunotherapeutic agents.
Fayen
J D
JD
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. jdf2@po.cwru.edu
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007378:Interleukins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011994:Recombinant Proteins; D014157:Transcription Factors; D023201:CD40 Ligand; D016572:Cyclosporine