Negative regulation by PD-L1 during drug-specific priming of IL-22–secreting T cells and the influence of PD-1 on effector T cell function

A Gibson, M Ogese, A Sullivan, E Wang… - The Journal of …, 2014 - journals.aai.org
A Gibson, M Ogese, A Sullivan, E Wang, K Saide, P Whitaker, D Peckham, L Faulkner…
The Journal of Immunology, 2014journals.aai.org
Activation of PD-1 on T cells is thought to inhibit Ag-specific T cell priming and regulate T cell
differentiation. Thus, we sought to measure the drug-specific activation of naive T cells after
perturbation of PD-L1/2/PD-1 binding and investigate whether PD-1 signaling influences the
differentiation of T cells. Priming of naive CD4+ and CD8+ T cells against drug Ags was
found to be more effective when PD-L1 signaling was blocked. Upon restimulation, T cells
proliferated more vigorously and secreted increased levels of IFN-γ, IL-13, and IL-22 but not …
Abstract
Activation of PD-1 on T cells is thought to inhibit Ag-specific T cell priming and regulate T cell differentiation. Thus, we sought to measure the drug-specific activation of naive T cells after perturbation of PD-L1/2/PD-1 binding and investigate whether PD-1 signaling influences the differentiation of T cells. Priming of naive CD4+ and CD8+ T cells against drug Ags was found to be more effective when PD-L1 signaling was blocked. Upon restimulation, T cells proliferated more vigorously and secreted increased levels of IFN-γ, IL-13, and IL-22 but not IL-17. Naive T cells expressed low levels of PD-1; however, a transient increase in PD-1 expression was observed during drug-specific T cell priming. Next, drug-specific responses from in vitro primed T cell clones and clones from hypersensitive patients were measured and correlated with PD-1 expression. All clones were found to secrete IFN-γ, IL-5, and IL-13. More detailed analysis revealed two different cytokine signatures. Clones secreted either FasL/IL-22 or granzyme B. The FasL/IL-22–secreting clones expressed the skin-homing receptors CCR4, CCR10, and CLA and migrated in response to CCL17/CCL27. PD-1 was stably expressed at different levels on clones; however, PD-1 expression did not correlate with the strength of the Ag-specific proliferative response or the secretion of cytokines/cytolytic molecules. This study shows that PD-L1/PD-1 binding negatively regulates the priming of drug-specific T cells. ELISPOT analysis uncovered an Ag-specific FasL/IL-22–secreting T cell subset with skin-homing properties.
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