PD‐1 regulation of pathogenic IL‐17‐secreting γδ T cells in experimental autoimmune encephalomyelitis

Abstract

AbstractThe PD‐1‐PD‐L1 immune checkpoint helps to maintain self‐tolerance and prevent the development of autoimmune diseases. Immune checkpoint inhibitors are successful immunotherapeutics for several cancers, but responding patients can develop immune‐mediated adverse events. It is well established that PD‐1 regulates CD4 and CD8 T‐cell responses, but its role in controlling the activation of pathogenic γδ T cells is less clear. Here we examined the role of PD‐1 in regulating γδ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We found that PD‐1 was highly expressed on CD27− Vγ4 γδ T cells in the lymph node (LN) and CNS of mice with EAE. Treatment of mice with anti‐PD‐1 significantly augmented IL‐17A‐producing CD27− Vγ4 γδ T cells in the LN and CNS and enhanced the severity of EAE. The exacerbating effect of anti‐PD‐1 on EAE was lost in Tcrd−/− mice. Conversely, ligation of PD‐1 suppressed Il17a and Rorc gene expression and IL‐17A production by purified Vγ4 γδ T cells stimulated via the TCR, but not with IL‐1β and IL‐23. Our study demonstrates that PD‐1 regulates TCR‐activated CD27− Vγ4 γδ T cells, but that cytokine‐activated IL‐17A producing γδ T cells escape the regulatory effects of the PD‐1‐PD‐L1 pathway.