P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus

Abstract

Altered control of T follicular helper (Tfh) cells can lead to generation of autoantibodies and autoimmune manifestations. Signaling pathways that selectively limit pathogenic responses without affecting the protective function of Tfh cells are unknown. Here we show that the ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant Tfh cells and the generation of self-reactive antibodies in experimental murine lupus, but its activity is dispensable for the expansion of antigen-specific Tfh cells during vaccination. P2X7 stimulation promotes caspase-mediated pyroptosis of Tfh cells and controls the development of pathogenic ICOS+ IFN-γ–secreting cells. Circulating Tfh cells from patients with systemic lupus erythematosus (SLE) but not primary antiphospholipid syndrome (PAPS), a nonlupus systemic autoimmune disease, were hyporesponsive to P2X7 stimulation and resistant to P2X7-mediated inhibition of cytokine-driven expansion. These data point to the P2X7 receptor as a checkpoint regulator of Tfh cells; thus, restoring P2X7 activity in SLE patients could selectively limit the progressive amplification of pathogenic autoantibodies, which deteriorate patients’ conditions.

Ecto-NTPDase CD39 is a negative checkpoint that inhibits follicular helper cell generation

“…In the intestinal environment, P2X7 stimulation reduces the number of Tfh cells in Peyer's patches (27). Similar results were found in disease models of malaria infection and systemic lupus erythematosus (28,29). In theory, CD39 could have a protective function in Tfh survival by reducing ATP and P2X signaling, if expressed in GCs.…”

Host–microbiota interactions in immune-mediated diseases

“…Conversely, certain MHC polymorphisms can select for a protective microbiota in immune-mediated diseases 126 . Furthermore, genetic alterations of the TLR7 pathway 11,127 or the ATP-gated cation channel P2X7 receptor 128,129 affect both host immunity and gut barrier function, thereby increasing the susceptibility to microbial translocation and autoimmunity 11 . These are only selected examples to illustrate the various scenarios where genetic risk factors predispose to immunological diseases in the context of the microbiota.…”

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

“…Diseases caused by Tfh cells can be divided into two distinct types: autoimmune diseases due to an overabundance of Tfh cells and immunodeficiencies due to a defect in the generation and functions of Tfh cells. One typical representative of autoimmune diseases is systemic lupus erythematosus (SLE), and these patients are found to have increased frequencies of Tfh-like cells in peripheral blood and an amplification of pathogenic autoantibodies [243,244]. Sjogren's syndrome (SS) [245], juvenile dermatomyositis [246], and rheumatism [247] are other common autoimmune diseases related to Tfh cells.…”