Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells

Abstract

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.