Bcl6 and Blimp1 reciprocally regulate ST2+ Treg–cell development in the context of allergic airway inflammation

Abstract

Background: Bcl6 is required for the development of T follicular helper and regulatory (Tfh, Tfr) cells that regulate germinal center responses. Bcl6 also impacts the function of regulatory T (Treg) cells. Objective:The goal of this study is to define the functions of Bcl6 in Treg cells including Tfr cells in the context of allergic airway inflammation (AAI). Methods: We employed a model of house dust mite (HDM) sensitization to challenge wild type, Bcl6 fl/fl Foxp3-Cre and Prdm1(Blimp1) fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in AAI. Results: In the HDM model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine producing cells in the lungs. In mice with Bcl6deficient Treg cells, twice as many ST2 (IL-33R) + Tregs develop as observed in wild type mice. ST2 + Tregs in the context of AAI are Blimp1-dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Tregs are more susceptible, and Blimp1-deficient Tregs are resistant, to acquiring the ST2 + Treg cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Tregs but not Bcl6-deficient ST2+ T conventional cells strongly promote AAI when transferred into recipient mice. Lastly, ST2 is required for the exacerbated AAI in Bcl6 fl/fl Foxp3-Cre mice. Conclusions: During AAI, Bcl6 and Blimp1 play dual roles in regulating Tfr activity in the germinal center and in the development of ST2 + Tregs that promote type 2 cytokine responses. Koh page 4 4 Key Messages: • Tfr cells limit IgE production in mice challenged by airway allergen • Bcl6 and Blimp1 reciprocally regulate ST2 + Treg development • ST2 + Tregs promote allergic airway inflammation Capsule Summary: Bcl6 attenuates allergic disease by promoting Tfr cell development to repress the allergen-specific humoral response and by limiting expansion of ST2 + Tregs.

IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation

“…Rivas et al found that enhancing IL-4R-STAT6 signaling decreased the formation of allergen-specific Treg in food allergy model 11 . IL-4 secreted by Th2 is enriched in allergic asthma 12 and are potent at promoting allergic inflammation 13 . However, the underlying mechanisms of IL-4 repressing Treg differentiation have not been clarified.…”

Mononuclear phagocyte regulation by the transcription factor Blimp‐1 in health and disease

“…62 Although no direct signalling pathway has been proposed, this suggests Blimp-1 functions downstream of ST2, which is in sharp contrast to cells in the T-cell lineage mentioned above. 37,38…”

“…Likewise, Blimp‐1 can stabilize the suppressive phenotype and correct localization of follicular Tregs, allowing them to inhibit germinal centre reactions 36 . However, the role of Blimp‐1 in follicular Tregs may be context‐dependent, as Blimp‐1 expression induces an ST2 + (Il1rl1, IL‐33R) allergy‐promoting phenotype of Tregs in the house dust mite model of allergic asthma 37 . Interestingly, Blimp‐1 shows particularly high expression levels in visceral adipose tissue Tregs in male mice, where it is induced in response to, and is essential to counteract, the low‐grade inflammatory signals sent by male visceral stroma.…”

“…Intriguingly, IL‐33 signalling through ST2 inhibits RANKL‐induced osteoclast differentiation of macrophage colony‐stimulating factor (M‐CSF)‐ and RANKL‐cultured bone marrow (BM)‐cells by downregulating Blimp‐1 mRNA while upregulating IRF8 expression 62 . Although no direct signalling pathway has been proposed, this suggests Blimp‐1 functions downstream of ST2, which is in sharp contrast to cells in the T‐cell lineage mentioned above 37,38 …”

“…36 However, the role of Blimp-1 in follicular Tregs may be context-dependent, as Blimp-1 expression induces an ST2 + (Il1rl1, IL-33R) allergy-promoting phenotype of Tregs in the house dust mite model of allergic asthma. 37 Interestingly, Blimp-1 shows particularly high expression levels in visceral adipose tissue Tregs in male mice, where it is induced in response to, and is essential to counteract, the low-grade inflammatory signals sent by male visceral stroma. In this context, Blimp-1 directly induces expression of the regulatory cytokine IL-10, the chemokine receptor CCR2 (essential for positioning the cells within CCL2-abundant fat), and ST2 (important for the expansion of the visceral fat Treg population).…”