JunB regulates homeostasis and suppressive functions of effector regulatory T cells

Abstract

Foxp3-expressing CD4+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. T-cell receptor (TCR)-dependent induction of the transcription factor IRF4 is essential for eTreg differentiation, but how IRF4 activity is regulated in Treg cells is still unclear. Here we show that the AP-1 transcription factor, JunB, is expressed in eTreg cells and promotes an IRF4-dependent transcription program. Mice lacking JunB in Treg cells develop multi-organ autoimmunity, concomitant with aberrant activation of T helper cells. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is also required for homeostasis and suppressive functions of eTreg. Mechanistically, JunB facilitates the accumulation of IRF4 at a subset of IRF4 target sites, including those located near Icos and Ctla4. Thus, JunB is a critical regulator of IRF4-dependent Treg effector programs, highlighting important functions for AP-1 in Treg-mediated immune homeostasis.

Regulatory T cells sense effector T‐cell activation through synchronized JunB expression

“…Consistent with the previous study, we found that JunB deficiency decreased the expression of genes encoding the Treg cell effector molecules, such as Icos, Klrg1, Ctla4, and Tigit. These results echo the conclusion in the previous study that JunB pIays an essential role in instructing the Treg effector program [15].…”

“…JunB deficiency caused massive immune cell infiltration into ears and salivary glands. However, we did not observe immune infiltrates in other tissues or organs as reported previously [15]. One possible explanation for this difference is that is that the Junb Flox/Flox mice used in the two studies are not the same.…”

“…On the other hand, siRNA-mediated knockdown of JunB and cJun does not affect Foxp3 expression [14]. Recently, one report shows that JunB regulates Tregmediated immunosuppression [15]. We notice that JunB is truncated but not completely deleted in Tregs of the mouse strain used in that study.…”

JunB controls intestinal effector programs in regulatory T cells

“…the “scurfy” phenotype 21 ). We also observed no spontaneous mortality (up to at least 14 weeks of age; data not shown), which contrasts markedly with the ∼35% lethality in Junb F/F Foxp3 YFP-cre mice reported by Koizumi et al 17 , suggesting that environmental differences may exert a substantial influence on JunB-dependent Treg activity. Taken together, these data suggest that JunB plays a nuanced role in Treg-mediated immune homeostasis.…”

“…Previously, we and others found that the AP-1 TF JunB was essential for the differentiation of inflammatory T-helper 17 (Th17) cells 14, 15, 16 , demonstrating that JunB plays subset-restricted roles in T cell programming. More recently, JunB was reported to control differentiation and suppressive functions of eTregs 17 ; however, many of the conclusions from this study are confounded by the use of a CD4-cre-mediated Junb conditional deletion strategy that has since been demonstrated to cause cell-extrinsic defects in Treg development 18 . Because of the predicted role of JunB in tissue-specific Tregs and previous data demonstrating broad and important roles for JunB in Th17 cells, we therefore chose to directly investigate whether JunB was important for tissue-specific functionality in Tregs.…”