Dual effect of CD85/leukocyte Ig-like receptor-1/Ig-like transcript 2 and CD152 (CTLA-4) on cytokine production by antigen-stimulated human T cells.
The functional outcome of a T cell response to Ag is the result of a balance between coactivation and inhibitory signals. In this study we have investigated the effects of the CD85/leukocyte Ig-like receptor (LIR)-1/Ig-like transcript (ILT) 2 and of CD152 (CTLA-4) inhibitory receptors on the modulation of cell-mediated immune responses to specific Ags, both at the effector and at the resting/memory cell level. Proliferation and cytokine production of CD4+ T lymphocytes stimulated by recall Ags have been evaluated. Cross-linking of CD85/LIR-1/ILT2 or CD152 molecules on cultured T cells using specific mAb and goat anti-mouse antiserum inhibits Ag-specific T cell proliferation. This inhibition is always paralleled by increased production of cytokines that down-regulate immune responses, e.g., IL-10 and TGF-beta. In contrast, the production of cytokines that support T cell expansion and function (e.g., IL-2, IFN-gamma, and IL-13) is significantly decreased. A long-term effect of CD85/LIR-1/ILT2 and of CD152 occurs during Ag-specific T cell activation and expansion. T cells, primed in the presence of anti-CD85/LIR-1/ILT2 and anti-CD152 blocking mAb (but in the absence of cross-linking), proliferate at higher rates and produce higher amounts of IL-2, IFN-gamma, and IL-13, in comparison with T cells stimulated with the Ag alone. We also show that the inhibitory receptors exert a similar effect during Ag activation of specific CD4+ effector T cells. Ag-specific polyclonal CD4+ T cell lines exhibit increased proliferation and IL-2, IFN-gamma, and IL-13 production when the CD85/LIR-1/ILT2 receptor is blocked by specific mAb. In contrast, cross-linking of this receptor down-regulates Ag-specific CD4+ T cell proliferation and increases IL-10 and TGF-beta production.
Saverino
Daniele
D
Department of Experimental Medicine, Human Anatomy Section, University of Genoa, Via De Toni 14, 16132 Genoa, Italy. Daniele.Saverino@unige.it
Merlo
Andrea
A
Bruno
Silvia
S
Pistoia
Vito
V
Grossi
Carlo E
CE
Ciccone
Ermanno
E
D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002453:Cell Cycle; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D018796:Immunoconjugates; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000494:pharmacology; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008213:Lymphocyte Activation; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007376:Interleukin-2; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic; D000069594:Abatacept