Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity

Abstract

The transcription factor Bach2 is a susceptible gene for numerous autoimmune diseases including systemic lupus erythematosus (SLE). Bach2−/− mice can develop a lupus-like autoimmune disease. However, the exact cellular and molecular mechanisms via which Bach2 protects the hosts from developing autoimmunity remains incompletely understood. Here, we report that Bach2 ablation on T cells, but not B cells, resulted in humoral autoimmunity, and this was associated with expansion of T follicular helper (Tfh) cells and abnormal germinal centers. Bach2 was down-regulated in Tfh cells and directly suppressed by the Tfh-defining transcription factor BCL6. Mechanistically, Bach2 directly suppresses the transcription of Cxcr5 and c-Maf, two key regulators of Tfh cell differentiation. Bach2-deficient Tfh cells were skewed toward the IL-4-producing subset, which induced IgG1 and IgE isotype switching of B cells. Heterozygous Bcl6 deficiency reduced the formation of germinal center and autoantibodies, and ameliorated the pathology in Bach2-deficient mice. Our findings identify Bach2 as a crucial negative regulator of Tfh cells at steady state and prove that Bach2 controls autoimmunity in part by restraining accumulation of pathogenic Tfh cells.

The Critical Role of Bach2 in Shaping the Balance between CD4+ T Cell Subsets in Immune-Mediated Diseases

“…Other studies have confirmed the association between some intronic SNPs and immunemediated diseases including celiac disease, type 1 diabetes, RA, and autoimmune Addison's disease [20,22]. Bach2 is downregulated and low expressed in Tfh cells [25,26]. Bach2 is a crucial negative regulator of Tfh cells to remain its steady state and restrain its pathogenic accumulation [25].…”

“…Bach2 can also directly downregulate the transcription of CXCR5 and c-Maf [26]. The deletion of Bach2 leads to the induction of CXCR5 expression even before the upregulation of Ascl2, which has been reported to initiate the Tfh cell differentiation programming and directly regulate CXCR5 expression [27,31].…”

“…The deletion of Bach2 results in preferential Tfh cell differentiation even enhanced non-Tfh cell effector functions [27]. And Bach2-deficient Tfh cells were altered to the IL-4producing subset, which induced IgG1 and IgE isotype switching of B cells [26]. Overexpression of Bach2 resulted in a fast loss of Tfh cell phenotype and subsequent breakdown of the GC response [25].…”

Immune responses during COVID-19 infection

“…Indeed, the authors revealed pathognomonic type I/II IFN responses during the acute-phase of SARS, those patients with oxygen saturation SO2>91% showed higher CXCL10 and CCL2 serum levels than those with SO2<91%. 82 However, sustained and relentless IFN responses that culminated in a dysfunctional adaptive immunity (deficient anti-SARS spike antibody production) were also observed in poor outcomes. 82 Chloroquine, by blocking the endosomal maturation, can reduce IFNαβ, and λ secretion by pDC and entail this type 1 IFN -related crisis.…”

“…82 However, sustained and relentless IFN responses that culminated in a dysfunctional adaptive immunity (deficient anti-SARS spike antibody production) were also observed in poor outcomes. 82 Chloroquine, by blocking the endosomal maturation, can reduce IFNαβ, and λ secretion by pDC and entail this type 1 IFN -related crisis. 83 Therefore, we surmise that the delicate regulation between the first wave of IFN (released by pDC), followed by bona fide cDC1 expected to efficiently prime airway CD4 + Th1 and Tc1 CTL and coincide with a productive TFH/B cell dialogue, is not occurring when secondary relays or influx of IFNs producing neutrophils and monocytes are recruited and/or when IL-10 producing regulatory T cells are missing.…”