Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens and maintain tissue homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently elucidated. We demonstrate here that PD-1 is an important negative regulator of KLRG1+ ILC-2 function in both mice and humans. Increase in KLRG1+ ILC-2 cell numbers was attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During Nippostrongylus brasiliensis infection, a significant expansion of KLRG1+ ILC-2 subsets occurred in Pdcd1−/− mice and, upon adoptive transfer, Pdcd1−/− KLRG1+ ILC-2s significantly reduced worm burden. Furthermore, blocking PD-1 with an antibody increased KLRG1+ ILC-2 cell number and reduced disease burden. Therefore, PD-1 is required for maintaining the number, and hence function, of KLRG1+ ILC-2s.

Programmed cell death-1 (PD-1; CD279) is a cell surface receptor that is expressed in both innate and adaptive immune cells. The role of PD-1 in adaptive immune cells, specifically in CD8⁺ T cells, has been thoroughly investigated but its significance in other immune cells is yet to be well established. This review will address the role of PD-1 based therapies in enhancing non-CD8⁺ T cell immune responses within cancer. Specifically, the expression and function of PD-1 in non-CD8⁺ immune cell compartments such as CD4⁺ T helper cell subsets, myeloid cells and innate lymphoid cells (ILCs) will be discussed. By understanding the immune cell specific function of PD-1 within tissue resident innate and adaptive immune cells, it will be possible to stratify patients for PD-1 based therapies for both immunogeneic and non-immunogeneic neoplastic disorders. With this knowledge from fundamental and translational studies, PD-1 based therapies can be utilized to enhance T cell independent immune responses in cancers.

Regulatory T (T_reg) cells are vital for immune suppression. The role of the coreceptor programmed cell death 1 receptor (PD-1) in T_reg cell function is controversial. Here, we demonstrate that PD-1 deficiency enhances the function of T_reg cells through expression of a compensatory network of coinhibitory receptors. CD30 has a central role within this network, driving the T_reg cell suppressive function within the tumor microenvironment. Mechanistically, PD-1 deficiency enhances STAT5 signaling in T_reg cells, which induces CD30 expression. These data indicate a role for PD-1 as a checkpoint that negatively controls CD30 expression in T_reg cells to limit their suppressive function. Understanding the functional changes that PD-1 has on T_reg cells might enable combination therapies with better treatment outcomes in cancer.

Programmed cell death-1 (PD-1) is a cell surface receptor that dampens adaptive immune responses. PD-1 is activated by the engagement of its ligands PDL-1 or PDL-2. This results in the inhibition of T cell proliferation, differentiation, cytokine secretion, and cytolytic function. Although a great deal is known about PD-1 mediated regulation of CD4⁺ and CD8⁺ T cells, its expression and function in innate lymphoid cells (ILCs) are yet to be fully deciphered. This review summarizes the role of PD-1 in (1) modulating ILC development, (2) ILC function, and (3) PD-1 signaling in ILC. Finally, we explore how PD-1 based immunotherapies may be beneficial in boosting ILC responses in cancer, infections, and other immune-related disorders.