Annexin V expression on CD4⁺ T cells with regulatory function

Regulatory T (Treg) cells induce immunologic tolerance by suppressing effector functions of conventional lymphocytes in the periphery. On the other hand, immune silencing is mediated by recognition of phosphatidylserine (PS) on apoptotic cells by phagocytes. Here we describe expression of the PS-binding protein Annexin V (ANXA5) in CD4⁺  CD25^hi Treg cells at the mRNA and protein levels. CD4⁺  ANXA5⁺ T cells constitute about 0·1%-0·6% of peripheral blood CD3⁺ T cells, exhibit co-expression of several Treg markers, such as Forkhead box P3, programmed cell death protein-1, cytotoxic T-lymphocyte antigen-4 and CD38. In vitro, ANXA5⁺ Treg cells showed enhanced adhesion to PS⁺ endothelial cells. Stimulated by anti-CD3 and PS⁺ syngeneic antigen-presenting cells CD4⁺  ANXA5⁺ T cells expanded in the absence of exogenous interleukin-2. CD4⁺  ANXA5⁺ T cells suppressed CD4⁺  ANXA5^- T-cell proliferation and mammalian target of rapamycin phosphorylation, partially dependent on cell contact. CD4⁺  ANXA5⁺ T-cell-mediated suppression was allo-specific and accompanied by an increased production of anti-inflammatory mediators. In vivo, using a model of delayed type hypersensitivity, murine CD4⁺  ANXA5⁺ T cells inhibited T helper type 1 responses. In conclusion, we report for the first time expression of ANXA5 on a subset of Treg cells that might bridge classical regulatory Treg function with immune silencing.