Adenosine receptor 2a agonists target mouse CD11c+T-bet+ B cells in infection and autoimmunity

Abstract

CD11c+T-bet+ B cells are recognized as an important component of humoral immunity and autoimmunity. These cells can be distinguished from other B cells by their higher expression of the adenosine receptor 2a. Here we address whether A2A receptor activation can affect CD11c+T-bet+ B cells. We show that administration of the A2A receptor agonist CGS-21680 depletes established CD11c+T-bet+ B cells in ehrlichial-infected mice, in a B cell-intrinsic manner. Agonist treatment similarly depletes CD11c+T-bet+ B cells and CD138+ B cells and reduces anti-nuclear antibodies in lupus-prone mice. Agonist treatment is also associated with reduced kidney pathology and lymphadenopathy. Moreover, A2A receptor stimulation depletes pathogenic lymphocytes and ameliorates disease even after disease onset, highlighting the therapeutic potential of this treatment. This study suggests that targeting the adenosine signaling pathway may provide a method for the treatment of lupus and other autoimmune diseases mediated by T-bet+ B cells.

ZEB2 regulates the development of CD11c+ atypical B cells

“…To further aid in studies of ABC development we also attempted to define conditions to induce ABCs in vitro (Figure 2F). In our hands we found that IL21 was critical for driving the development of a CD11c + CD21cells in vitro after stimulation with anti-CD40 (Figure 2G-H), consistent with previous reports about the essential role of IL21 in ABC development (20,(31)(32)(33). Based on our analysis of tonsil single cell dataset we further found that ABCs expressed many genes in the TGFβ signalling pathway (Figure S2E-F).…”

“…Cells in this ABC cluster also had the highest surface expression of FCRL4, CD11c and CD19 by CITE-seq analysis (Figure 1D). Data has been conflicting on whether ABC formation is dependent on the GC (20,26), therefore we performed VDJ analysis on identified clusters and we found ABCs were not notably different from cMBCs with respect to their antibody isotype usage (Figure S1C). Moreover, they had only marginally lower frequencies of somatic hypermutation (SHM) compared to cMBCs and GC B cells (Figure S1D), though SHM inversely correlated with the strength of expression of ABC genes (Figure S1E).…”

“…The robustness of this method was further confirmed by the nearly complete abolishment of GC B cells in the transferred Bcl6KO GFP -Igh g2A10 cells following PfCSP-SPZ immunization (Figure S3F-H). Because previous studies have been conflicting on whether ABC formation requires GC (20,26), we further analyzed the percentages of ABCs in memory Igh g2A10 B cells and found Bcl6 was not required for ABC formation (Figure S3G, S3I). Interestingly, we found GFP KO mildly but significantly affects ABC formation (Figure S3G, S3I).…”

“…However in animal models of systemic lupus erythematosus (SLE) Tbet has been found to be dispensable for disease progression and the formation of CD11c + CD11b + ABCs (18,19). Moreover, in an E. muris model of infection CD19 hi CD11c + ABCs formed normally in Tbet knockout animals (20).…”

Epstein–Barr virus infection, B‐cell dysfunction and other risk factors converge in gut‐associated lymphoid tissue to drive the immunopathogenesis of multiple sclerosis: a hypothesis

“…Such investigations may lead to more targeted therapies for modulating B‐cell dysfunction. For example, therapeutic inhibition of adenosine receptor 2a on CD11c + /T‐bet + MBCs 159 is potentially a means of decreasing pathogenic B‐cell responses without impairing global B‐cell function. Future investigations of the gut microbiota and/or SCFAs in studies of MS pathogenesis should include analyses of the relationship with EBV reactivation and activation of circulating MBCs, particularly MZ B cells.…”