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

Fabienne Mazerolles,Frédéric Rieux-Laucat,Pierre Bobé

doi:10.1371/journal.pone.0260206

Fabienne Mazerolles, Frédéric Rieux-Laucat + Show 1 more

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https://doi.org/10.1371/journal.pone.0260206

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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.

Highlights

A large number of co-signalling molecules are involved in the production of co-stimulatory or co-inhibitory signals in the regulation of T cell activation
By using distinct cell tracers, we could simultaneously assess the expression of receptors on carboxyfluorescein succinimidyl ester (CFSE)-stained regulatory T cells (TREGs) and CellTraceTM Violet (CTV)-stained effector CD4+ T cells (TEFFs) co-cultured with DCs and staphylococcal enterotoxin E (SEE) on D4, day 5 (D5) and D7 (Fig 5)
T cell immunoglobulin and ITIM domain (TIGIT) expression was never detected on TEFFs co-cultured with DCs in the absence or in the presence of TREGs—showing that the absence of TIGIT expression on TEFFs was not linked to inhibition by TREGs (S5B Fig)

Summary

Introduction

A large number of co-signalling molecules are involved in the production of co-stimulatory or co-inhibitory signals in the regulation of T cell activation. TIGIT is expressed in immune cells, where it acts as a co-inhibitory receptor in parallel to the CD28/CTLA-4 pathway [14] In both humans and mice, TIGIT is highly expressed on a subset of natural TREG and marks an activated TREG phenotype [15]. TIM3 (a member of the TIM family of immune regulatory receptors) is expressed predominantly on Th1 cells and on Th17 cells It appears to be a co-inhibitory molecule for T cell function [28] but is weakly expressed by conventional CD4+ T cells and by TREGs in the peripheral blood [31].

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