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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.
Highlights
forkhead box P3 (Foxp3)-expressing CD4+ regulatory T (Treg) cells need to differentiate into effector Treg cells to maintain immune homeostasis
We assessed whether there is a correlation between JunB expression and distinct Treg subpopulations. central Treg (cTreg) cells circulate through secondary lymphoid organs, whereas effector Treg (eTreg) cells preferentially accumulate in peripheral tissues[6,14,24]
Consistent with enrichment of JunB-expressing Treg cells in the lung, we found that JunB was expressed in eTreg cells, but not in cTreg cells in spleen (Fig. 1c). eTreg cells heterogeneously express surface molecules such as inducible T-cell costimulator (ICOS), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and killer cell lectin-like receptor 1 (KLRG1)[11,18,24,46,47,48,49]
Summary
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. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is required for homeostasis and suppressive functions of eTreg. 1234567890():,; Regulatory T (Treg) cells can suppress a variety of immune responses and contribute to immune homeostasis[1,2] They require the lineage-specifying transcription factor, forkhead box P3 (Foxp3), for development, maintenance of cell identity, and suppressive functions[3,4,5]. ETreg cells express higher levels of Treg effector molecules, such as inducible T-cell costimulator (ICOS) and cytotoxic T-cell-associated antigen 4 (CTLA4), than do cTreg cells, which are likely important for eTreg-suppressive functions and homeostasis[7,14,16,17,18]. We show crucial functions for JunB in the IRF4-dependent eTreg transcriptional program
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