PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2

Abstract

Programmed death‐1 (PD‐1) is an immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐containing receptor expressed upon T cell activation. PD‐1^–/– animals develop autoimmune diseases, suggesting an inhibitory role for PD‐1 in immune responses. Members of the B7 family, PD‐L1 and PD‐L2, are ligands for PD‐1. This study examines the functional consequences of PD‐1:PD‐L engagementon murine CD4 and CD8 T cells and shows that these interactions result in inhibition of proliferation and cytokine production. T cells stimulated with anti‐CD3/PD‐L1.Fc‐coated beads display dramatically decreased proliferation and IL‐2 production, while CSFE analysis shows fewer cells cycling and a slower division rate. Costimulation with soluble anti‐CD28 mAb can overcome PD‐1‐mediated inhibition by augmenting IL‐2 production. However, PD‐1:PD‐L interactions inhibit IL‐2 production even in the presence of costimulation and, thus, after prolonged activation, the PD‐1:PD‐L inhibitory pathway dominates. Exogenous IL‐2 is able to overcome PD‐L1‐mediated inhibition at all times, indicating that cells maintain IL‐2 responsiveness. Experiments using TCR transgenic CD4⁺ or CD8⁺ T cells stimulated with antigen‐presenting cells expressing PD‐L1 show that both T cell subsets are susceptible to this inhibitory pathway. However, CD8⁺ T cells may be more sensitive to modulation by the PD‐1:PD‐L pathway because of their intrinsic inability to produce significant levels of IL‐2.