Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells.
CD28 and CTLA-4 are opposing regulators of T cell activation, triggered by the two ligands CD80 and CD86. How these ligands promote either T cell activation via CD28 or inhibition via CTLA-4 is not understood. Using CD80 and CD86 molecules expressed on transfected cells, we have identified a major difference between these ligands in that CD80 transfectants have the ability to inhibit activation of resting human peripheral blood T cells via interaction with CTLA-4, whereas CD86 transfectants do not. Rather, CTLA-4-CD86 interactions appear to contribute towards T cell proliferation. We also observed that CTLA-4 function is strongly influenced by TCR stimulation, effects being observed only at relatively low levels of TCR stimulation. The kinetics of CD80-CTLA-4 interactions revealed that CTLA-4 inhibition took place within the first 8 h of T cell stimulation, despite there being little measurable CTLA-4 expression on the majority T cells. However, significant amounts of CTLA-4 were observed in the CD25(+) CD4(+) subset of T cells which, when removed from the cultures, accounted for the CTLA-4 inhibition observed. Overall, these data provide evidence that CD80 and CD86 differ in their interactions with CTLA-4 and that CD80 appears to be the preferential inhibitory ligand for CTLA-4 working via a population of CD4(+) CD25(+) CTLA-4(+) regulatory T cells.
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D000943:Antigens, Differentiation / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology; D016466:CHO Cells; D060908:CTLA-4 Antigen; D006224:Cricetinae; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D000069594:Abatacept