Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Abstract

Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1 −/− ) develop spontaneous autoimmune diseases. PD-1 −/− mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1 −/− mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1 −/− recombination activating gene (RAG)2 −/− mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1 +/+ RAG2 −/− mice. This result suggested PD-1's involvement in the regulation of innate immune responses. Mice reconstituted with PD-1 −/− RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells developed more severe EAE compared with the ones reconstituted with PD-1 +/+ RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells. We found that upon recognition of HKMTB, CD11b + macrophages from PD-1 −/− mice produced very high levels of IL-6, which helped promote naive CD4 + T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells.autoimmunity | inflammation

Programmed Death-1 Culls Peripheral Accumulation of High-Affinity Autoreactive CD4 T Cells to Protect against Autoimmunity

“…In turn, infiltration of the brain and spinal cord by autoreactive CD4 T cells with the highest MOG affinity was unleashed in PD-1 deficient mice after MOG administration in complete Freund’s adjuvant (Figures 1B and S2). This necessity for PD-1 in dampening the activation of high affinity self-reactive CD4 T cells likely explains why the severity and incidence of EAE are both sharply exacerbated in the absence of PD-1 (Figure 1C) (Rui et al, 2013; Salama et al, 2003). …”

“…Human polymorphisms that diminish PD-1 activity similarly increase the risk of autoimmune disorders such as systemic lupus erythematosus and multiple sclerosis (Kroner et al, 2005; Prokunina et al, 2002). In turn, mice deficient in PD-1 are also more susceptible to developing a variety of autoimmune disorders including dilated cardiomyopathy, neuronal demyelination, diabetes, arthritis and glomerulonephritis (Nishimura et al, 1999; Nishimura et al, 2001; Rui et al, 2013; Wang et al, 2005). Given this critical role for PD-1 in protection against autoimmunity in humans and rodent disease models, we sought to further investigate how this co-inhibitory molecule controls the activation and peripheral accumulation of autoreactive T cells.…”

Genetic and Epigenetic Regulation of PD-1 Expression

“…The immune inhibitory function of PD-1 was demonstrated in PD-1 and PD-L1 knock-out mice, which presented hyperactive immune phenotypes (4, 7, 8), and mutations in PD-1 have been associated with disease progression in multiple human autoimmune disorders (9–11). High levels of PD-1 were linked to CD8 T cell exhaustion during chronic viral infections (5, 6, 12–18).…”

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

“…Further supporting IL-17 signaling as a resistance mechanism to PD-1 blockade, Rui and colleagues found that an increased response of PD-1 knockout mice to heat-killed mycobacteria resulted in enhanced production of Th17 cells [194]. A causal relationship between PD-1 signaling and IL-17 response is suggested by the fact that tuberculosis patients were found to have increased numbers of PD-1+ T-cells compared with healthy individuals, and in this case, CD4+ T-cells secreted less IL-17 [195].…”