Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation.
The direct effects of IL-10 on the proliferation and lymphokine production of human peripheral blood T cells and CD4+ T cell clones representing the Th0, Th1-like, and Th2-like Th cell subsets were investigated in the absence of professional APC. IL-10 partially inhibited the proliferative responses of CD4+ human T cell clones induced by anti-CD2 or anti-CD3 mAb cross-linked on CD32 (Fc gamma RII)-transfected mouse L cells. Transfection of ICAM-1 or LFA-3 in CD32+ L cells resulted in enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD3 mAb, whereas transfection of B7 in CD32+ L cells enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD2 mAb. In addition, B7 expression on CD32+ L cells was required for activation of small resting T cells by anti-CD3 or anti-CD2 mAb. IL-10 inhibited the proliferation of T cell clones induced by anti-CD2 or anti-CD3 mAb on CD32+ L cells expressing these accessory molecules, indicating that interactions of LFA-3, ICAM-1, and B7 with their ligands on T cells did not overcome the inhibitory effects of IL-10. Inhibition of proliferation of T cell clones by IL-10 was in all instances completely neutralized by relatively low concentrations of IL-2, whereas IL-4 was ineffective. IL-10 did not affect the expression of the TCR/CD3 complex, CD2, LFA-1, CD28, or IL-2R alpha- or beta-chains, nor did it inhibit the induction of the latter two molecules on T cells after activation. Inhibition of proliferation was found to be the result of specific inhibition of IL-2 production by the responding T cell subsets, which occurred at the mRNA level. The production and mRNA levels of IL-4, IL-5, IFN-gamma, and granulocyte/macrophage-CSF were not affected by IL-10. Taken together, these results indicate that IL-10/IL-10R interaction on CD4+ T cell clones and peripheral blood T cells results in signaling pathways that specifically interfere with activation processes leading to IL-2 production. These direct inhibitory effects on IL-2 production by activated T cells may contribute to the general immunosuppressive activities of IL-10.
de Waal Malefyt
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DNAX Research Institute, Human Immunology Department, Palo Alto, CA 94304.
Yssel
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de Vries
J E
JE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D000954:Antigens, Surface / Q000502:physiology; D018122:B7-1 Antigen; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules / Q000502:physiology; D002999:Clone Cells; D003432:Cross-Linking Reagents; D016207:Cytokines / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007739:L Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D017452:Receptors, IgG / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D018122:B7-1 Antigen; D017252:CD3 Complex; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; D016207:Cytokines; D006131:Growth Inhibitors; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D015847:Interleukin-4