PD‐1 signalling in CD4+ T cells restrains their clonal expansion to an immunogenic stimulus,but is not critically required for peptide‐induced tolerance

The ultimate outcome of T‐cell recognition of peptide–major histocompatibility complex (MHC) complexes is determined by the molecular context in which antigen presentation is provided. The paradigm is that, after exposure to peptides presented by steady‐state dendritic cells (DCs), inhibitory signals dominate, leading to the deletion and/or functional inactivation of antigen‐reactive T cells. This has been utilized in a variety of models providing peptide antigen in soluble form in the absence of adjuvant. A co‐inhibitory molecule of considerable current interest is PD‐1. Here we show that there is the opportunity for the PD‐1/PD‐L1 interaction to function in inhibiting the T‐cell response during tolerance induction. Using traceable CD4⁺ T‐cell receptor (TCR) transgenic cells, together with a blocking antibody to disrupt PD‐1 signalling, we explored the roles of PD‐1 in the induction of tolerance versus a productive immune response. Intact PD‐1 signalling played a role in limiting the extent of CD4⁺ T‐cell accumulation in response to an immunogenic stimulus. However, PD‐1 signalling was not required for either the induction, or the maintenance, of peptide‐induced tolerance; a conclusion underlined by successful tolerance induction in TCR transgenic cells genetically deficient for PD‐1. These observations contrast with the reported requirement for PD‐1 signals in CD8⁺ T‐cell tolerance.