Bcl6 promotes follicular helper T‐cell differentiation and PD‐1 expression in a Blimp1‐independent manner in mice

Xie, Markus M.; Koh, Byung Hee; Hollister, Kristin; Wu, Hao; Sun, Jie; Kaplan, Mark H.; Dent, Alexander L.

doi:10.1002/eji.201747034

Cited by 33 publications

(41 citation statements)

References 28 publications

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“…Foxp3-Yfp-cre only (WT) and Foxp3-Yfp-cre Bcl6-flox (Bcl6FC) mice were previously described (7,29). Prdm1-flox mice (30) were crossed with Bcl6FC transgenic mice to generate Foxp3-Yfp-cre Prdm1-flox (Blimp1FC) and Foxp3-YFP-cre Prdm1-flox Bcl6-flox (DKO) mice. Male and female mice 6-10 weeks old were used.…”

Section: Methodsmentioning

confidence: 99%

Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells

Xie¹,

Fang²,

Chen³

et al. 2019

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Section: Methodsmentioning

confidence: 99%

Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells

Xie¹,

Fang²,

Chen³

et al. 2019

JCI Insight

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“…7e, f). Based on recent literature showing that Bcl6 promotes PD-1 expression in T FH cells 30,31 we asked in which of our models PD-1 may be downregulated as well. Strikingly, only in the CIA and NP-CGG immunized mice, ethanol and acetate exposure reduced PD-1 expression (MFI level) ( Figs.…”

Section: Il-21 Reverses Arthritis-mitigating Effect Of Alcoholmentioning

confidence: 99%

Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis

et al. 2020

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Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this toleranceinducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (T FH ) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by T FH cells, preventing proper spatial organization of T FH cells to form T FH :B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and toleranceinducing effect of alcohol consumption.

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“…(Minnich et al, 2016;Xie et al, 2017). This effect 338 was greater in Tregs than in effector T cells (Fig 9E).…”

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confidence: 66%

Blimp-1 is essential for Th2 cell development and allergic asthma

Hettinga

Kale

et al. 2019

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The transcriptional repressor Blimp-1 acts via a pro-inflammatory IL-10-17 STAT3 axis as a critical positive regulator of Th2 cells in the lung in response to 18 allergens driving pathophysiology associated with asthma disease. 19 20 Abstract 21 A Th2 immune response is central to allergic airway inflammation, which afflicts millions 22worldwide. However, the mechanisms that augment GATA3 expression in an antigen-23 to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by 33 promoting rather than terminating effector T cell responses. 34 35 1997). However, the signals that support this process in vivo are still not well death, suggesting Blimp-1 also controls effector responses by limiting effector cell 70 numbers directly (Poholek et al., 2016). 71Our previous studies showed that disrupting Blimp-1 in T cells increased Th2 responses 72 in a worm antigen model. Therefore, we hypothesized that T cell specific deficiency of 73Blimp-1 in an allergic airway inflammation model would lead to increased expansion of 74 effector cells and more severe disease due to increased Th2 responses. Unexpectedly, 75we found that T cell specific Blimp-1 deficiency protected mice from the development of 76 allergic lung inflammation and Th2 cells in the lung were severely reduced. STAT3 via 77 IL-10 was required for Blimp-1 expression and Th2 cell development in this model, 78suggesting IL-10 may play an unexpected role in supporting Th2 cell differentiation. 79Mechanistically, our data supports an intrinsic role for Blimp-1 mediated repression of 80 Bcl6, which in turn can repress GATA3. Thus, Blimp-1 indirectly supports Th2 81 differentiation by promoting GATA3 expression. These data identify a new context-82 dependent role for Blimp-1 in T cells that is essential for the full development of allergic 83 lung disease, highlighting a previously unappreciated pathway with potential therapeutic 84 targets for the treatment of asthma disease. 85 86Results 87 Blimp-1 in T cells promotes allergic airway inflammation 88Blimp-1 controls effector T cell responses and constrains autoimmunity (Crotty et al., 89 2010; Poholek et al., 2016). We reasoned that during a house dust mite (HDM) induced 90 model of allergic lung disease, the absence of Blimp-1 in T cells would drive increased 91 effector T cells and exacerbate disease. To test this, we compared mice in which Blimp-92 the lung and mLN (Fig 1E,F, S1C), suggesting that the absence of Blimp-1 in T cells 130 resulted in a concomitant increase in Bcl6. Together, these data suggest that Blimp-1 131 plays a surprising and critical role in driving the differentiation of Th2 cells in response to 132 inhaled allergens that is necessary for resulting inflammation in the lung tissue. 133 134 IgE responses are Blimp-1 independent 135A hallmark of type2 driven allergic responses is the presence of high levels of circulating 136IgE. In contrast to the decrease in type2 immunity observed in the lungs of Blimp-1 CD4Cre 137 animals (reduced Th2 cells and eosinophils in BAL)...

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Bcl6 promotes follicular helper T‐cell differentiation and PD‐1 expression in a Blimp1‐independent manner in mice

Cited by 33 publications

References 28 publications

Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells

Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells

Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis

Blimp-1 is essential for Th2 cell development and allergic asthma

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