T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton’s tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.

Proper control of immune responses by Foxp3+ regulatory T cells at inflamed sites is crucial for the prevention of immunopathology. TGF‐β‐induced Foxp3+ regulatory T (Treg) cells are generated in inflammatory environments as well as in steady‐state conditions. Inflammatory cytokines such as IFN‐γ and IL‐4 have an antagonistic effect on Treg cell conversion. However, it is not known how naive CD4+ T cells overcome the inhibitory environment in inflamed sites to differentiate into Treg cells. Here, we show that CCAAT/enhancer‐binding protein (C/EBP) functions as a safeguard that enhances Treg cell generation by dampening the inhibitory effect of IFN‐γ and IL‐4 on Foxp3 expression. We find that C/EBPβ is induced by retinoic acid and binds to the methyl‐CRE sequence in the Foxp3 TSDR to sustain its expression. C/EBPβ‐transduced iTreg cells show more potent suppressive activity in mouse disease models. We also reveal that C/EBPβ‐transduced human iTreg cells exhibit more enhanced suppressor function. These results establish C/EBP as a new molecular target for enhancing the formation and stability of Treg cells in inflammatory environments.

Epigenetic regulation, including chromatin accessibility and posttranslational modifications of histones, is of importance for T cell lineage decision. T H 17 cells play a critical role in protective mucosal immunity and pathogenic multiple autoimmune diseases. The differentiation of T H 17 cells is dictated by a master transcription factor, RORgt. However, the epigenetic mechanism that controls T H 17 cell differentiation remains poorly understood. Here we show that the Swi/Snf complex is required for T H 17-mediated cytokine production both in vitro and in vivo. We demonstrate that RORgt recruits and forms a complex with the Swi/Snf complex to cooperate for the RORgt-mediated epigenetic modifications of target genes, including both permissive and repressive ones for T H 17 cell differentiation. Our findings thus highlight the Swi/Snf complex as an essential epigenetic regulator of T H 17 cell differentiation and provide a basis for the understanding of how a master transcription factor RORgt collaborates with the Swi/ Snf complex to govern epigenetic regulation.

Activated Foxp3 + regulatory T (Treg) cells differentiate into effector Treg (eTreg) cells to maintain peripheral immune homeostasis and tolerance. T cell receptor (TCR)–mediated induction and regulation of store-operated Ca 2+ entry (SOCE) is essential for eTreg cell differentiation and function. However, SOCE regulation in Treg cells remains unclear. Here, we show that inositol polyphosphate multikinase (IPMK), which generates inositol tetrakisphosphate and inositol pentakisphosphate, is a pivotal regulator of Treg cell differentiation downstream of TCR signaling. IPMK is highly expressed in TCR-stimulated Treg cells and promotes a TCR-induced Treg cell program. IPMK-deficient Treg cells display aberrant T cell activation and impaired differentiation into RORγt + Treg cells and tissue-resident Treg cells. Mechanistically, IPMK controls the generation of higher-order inositol phosphates, thereby promoting Ca 2+ mobilization and Treg cell effector functions. Our findings identify IPMK as a critical regulator of TCR-mediated Ca 2+ influx and highlight the importance of IPMK in Treg cell-mediated immune homeostasis.

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