The Trypanosoma cruzi membrane mucin AgC10 inhibits T cell activation and IL-2 transcription through L-selectin.
Trypanosoma cruzi infection is associated with a severe T cell unresponsiveness to antigens and mitogens characterized by a decreased IL-2 synthesis and by nitric oxide (NO) production. Although spleen cell unresponsiveness to ConA was less severe in infected IFN-gammaR-/- or inducible nitric oxide synthase (iNOS)-/- mice than in control littermates, IL-2 inhibition was as severely impaired. Ag C10, a T. cruzi mucin, inhibited T cell proliferation as well as IL-2 secretion and IL-2 mRNA induction in response to mitogens and to anti-CD3. This effect took place at the transcriptional level since Ag C10 was able to inhibit IL-2 promoter-driven transcription. Moreover, the transcription of reporter genes controlled by CD28RE, NFAT or AP-1, but not by NF-kappaB sites, were inhibited by AgC10 to different degrees, although the greatest effect was observed for NFAT. In agreement with that, overexpression of NFAT significantly reverted Ag C10 inhibition of IL-2 transcription. AgC10 also inhibited early steps of T cell activation as tyrosine phosphorylation of the tyrosine kinase ZAP-70 and the adapter protein SLP-76. AgC10 binds to T cell surface through CD62L, and antibodies to CD62L inhibited T cell proliferation and IL-2 secretion and transcription as efficiently as AgC10. Indeed, AgC10 did not inhibit activation by T cells from CD62L-deficient mice (Sell-/-). Our results suggest that Ag C10, through binding to L-selectin, was able to inhibit different activation pathways that lead to inhibition of IL-2 secretion and T cell proliferation. This was independent of NO and IFN-gamma.
Alcaide
Pilar
P
Centro de Biología Molecular (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049 Spain.
Fresno
Manuel
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007376:Interleukin-2 / Q000378:metabolism*; D019169:Jurkat Cells; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D009077:Mucins / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D014349:Trypanosoma cruzi / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D000953:Antigens, Protozoan; D007376:Interleukin-2; D009077:Mucins; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D014157:Transcription Factors; D019041:L-Selectin; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse