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Abstract
Type 1 regulatory T (Tr1) cells are subset of peripherally induced antigen-specific regulatory T cells. IL-10 signaling has been shown to be indispensable for polarization and function of Tr1 cells. However, the transcriptional machinery underlying human Tr1 cell differentiation and function is not yet elucidated. To this end, we performed RNA sequencing on ex vivo human CD49b+LAG3+ Tr1 cells. We identified the transcription factor, BHLHE40, to be highly expressed in Tr1 cells. Even though Tr1 cells characteristically produce high levels of IL-10, we found that BHLHE40 represses IL-10 and increases IFN-γ secretion in naïve CD4+ T cells. Through CRISPR/Cas9-mediated knockout, we determined that IL10 significantly increased in the sgBHLHE40-edited cells and BHLHE40 is dispensable for naïve CD4+ T cells to differentiate into Tr1 cells in vitro. Interestingly, BHLHE40 overexpression induces the surface expression of CD49b and LAG3, co-expressed surface molecules attributed to Tr1 cells, but promotes IFN-γ production. Our findings uncover a novel mechanism whereby BHLHE40 acts as a regulator of IL-10 and IFN-γ in human CD4+ T cells.
Highlights
Regulatory T (Treg) cells are multifaceted immunomodulatory cells that are composed of two subgroups: thymus- and peripherally- derived [1]
To understand the transcriptome of ex vivo human Tr1 cells in an unbiased, high-throughput approach, we RNA-sequenced sorted Tr1 cells with the CD3+CD4+CD45RA-CD49b+LAG3+ phenotype (Figure 1A; Q2 outlined in red), and the non-Tr1 memory T cells (Tmem; CD3+CD4+CD45RA-CD49b-LAG3-; Figure 1A; Q4 outlined in black) directly from the peripheral blood of healthy donors without any in vitro activation
Our collective results delineate the role of the transcription factor, Basic Helix-Loop-Helix Family Member E40 (BHLHE40), using in vitro-induced models of human Tr1 cells and CD4+ T cells
Summary
Regulatory T (Treg) cells are multifaceted immunomodulatory cells that are composed of two subgroups: thymus- and peripherally- derived [1]. Type 1 regulatory T (Tr1) cells are a peripherallyderived subset that is induced under tolerogenic conditions in an antigen-specific manner [2]. Tr1 cells regulate the function of other T cells directly and indirectly through antigen presenting cells predominately by secreting high levels of the pleiotropic cytokine IL-10 [3,4,5]. Unlike other IL-10 producing T helper cells, such as Th2 and Th17 cells, Tr1 cells have a unique cytokine profile: high IL-10 and TGF-b, low IL-2, no IL-4 and IL-17, and variable amounts of IFN-g [2]. Besides IL-10 production, murine and human Tr1 cells can be identified by the co-expression of CD49b and LAG3 [5]. Sole expression of either LAG3 or CD49b is insufficient to identify Tr1 cells because these
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