Transient T-bet expression functionally specifies a distinct T follicular helper subset

Abstract

T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN-γ without expressing the Th1 transcription factor T-bet. Whether this IFN-γ-producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood. By using T-bet fate-mapping mouse strains, we discovered that almost all the IFN-γ-producing Tfh cells have previously expressed T-bet and express high levels of NKG2D. DNase I hypersensitivity analysis indicated that the gene locus is partially accessible in this "ex-T-bet" population with a history of T-bet expression. Furthermore, multicolor tissue imaging revealed that the ex-T-bet Tfh cells found in germinal centers express IFN-γ in situ. Finally, we found that IFN-γ-expressing Tfh cells are absent in T-bet-deficient mice, but fully present in mice with T-bet deletion at late stages of T cell differentiation. Together, our findings demonstrate that transient expression of T-bet epigenetically imprints the locus for cytokine production in this Th1-like Tfh cell subset.

T follicular helper cell heterogeneity: Time, space, and function

“…This subset of Tfh cells has been confirmed by fatetracking experiments, which further demonstrated that Tfh cells that previously expressed T-bet become IFNγ-producing GC Tfh cells 100. IFNγ production by Tfh cells is dependent on STAT4 signaling, which presumably leads to T-bet-dependent and -independent chromatin remodeling at the Ifng locus to retain accessibility even after T-bet expression is lost 99,100. In type 1 infection settings such as influenza and Plasmodium chabaudi, a population of IFNγ and IL-21 double producing T cells confer protection in part through facilitating humoral immunity yet are able to retain their cytokine production profile even in the absence of Bcl6 101,102.…”

“…A population of early Tfh cells also co-express IFNγ and IL-21 and have similar level of T-bet expression as Th1 cells 99. This subset of Tfh cells has been confirmed by fatetracking experiments, which further demonstrated that Tfh cells that previously expressed T-bet become IFNγ-producing GC Tfh cells 100. IFNγ production by Tfh cells is dependent on STAT4 signaling, which presumably leads to T-bet-dependent and -independent chromatin remodeling at the Ifng locus to retain accessibility even after T-bet expression is lost 99,100.…”

T‐bet+ memory B cells: Generation, function, and fate

“…The association of T-bet with IgG1 switching suggests these cells previously expressed T-bet or are derived from T-betexpressing progenitors; in line with this possibility, a recent study identified a subset of Tfh cells that transiently expresses T-bet but retains the capacity to perform T-bet-regulated functions such as IFNγ production 91. The association of T-bet with IgG1 switching suggests these cells previously expressed T-bet or are derived from T-betexpressing progenitors; in line with this possibility, a recent study identified a subset of Tfh cells that transiently expresses T-bet but retains the capacity to perform T-bet-regulated functions such as IFNγ production 91.…”

Regulation of IgE by T follicular helper cells

“…105,106 Although not considered canonical Tfh TFs, multiple studies have since observed that Tfh cells can co-express other lineage TFs such as T-bet and GATA3 along with BCL6 and make cytokines such as IFN or IL-13 during particular type 1 or 2 immune responses. 15,88,[107][108][109][110] Our recent analysis of single-cell RNA-sequencing of Tfh cells induced to the allergen Alternaria alternata showed that IL-13 + IL-4 + Tfh13 cells expressed high levels of Gata3 whereas the IL-4 + Tfh2 cells did not. Therefore, Gata3 up-regulation could be a key determinant in inducing IL-5 and -13 in addition to IL-4 production in Tfh13 cells.…”