PD-L1 is expressed on human activated naive effector CD4+ T cells. Regulation by dendritic cells and regulatory CD4+ T cells

Abstract

The T cell expression of various co-signalling receptors from the CD28 immunoglobulin superfamily (Inducible T cell co-stimulator (ICOS), Programmed cell death 1(PD-1), cytotoxic T lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte attenuator (BTLA) or from the tumour necrosis factor receptor superfamily (glucocorticoid-induced TNFR family related (GITR), 4-1BB, and CD27), is essential for T cell responses regulation. Other receptors (such as T cell immunoglobulin and mucin domain-containing protein 3, T cell immunoglobulin and T cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene 3) are also involved in this regulation. Disturbance of the balance between activating and inhibitory signals can induce autoimmunity. We have developed an in vitro assay to simultaneously assess the function of naive CD4+ effector T cells (TEFFs), dendritic cells (DCs) and regulatory T cells (TREGs) and the expression of co-signalling receptors. By running the assay on cells from healthy adult, we investigated the regulation of activated T cell proliferation and phenotypes. We observed that TEFFs activated by DCs mainly expressed BTLA, ICOS and PD-1, whereas activated TREGs mainly expressed TIGIT, ICOS, and CD27. Strikingly, we observed that programmed death-ligand 1 (PD-L1) was significantly expressed on both activated TEFFs and TREGs. Moreover, high PD-L1 expression on activated TEFFs was correlated with a higher index of proliferation. Lastly, and in parallel to the TREG-mediated suppression of TEFF proliferation, we observed the specific modulation of the surface expression of PD-L1 (but not other markers) on activated TEFFs. Our results suggest that the regulation of T cell proliferation is correlated with the specific expression of PD-L1 on activated TEFFs.