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Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease

ABSTRACT: Regulatory T (Treg) cells suppress the development of inflammatory disease, but our knowledge of transcriptional regulators that control this function remains incomplete. Here we show that expression of Id2 and Id3 in Treg cells was required to suppress development of fatal inflammatory disease. We found that T cell antigen receptor (TCR)-driven signaling initially decreased the abundance of Id3, which led to the activation of a follicular regulatory T (TFR) cell–specific transcription signature. However, sustained lower abundance of Id2 and Id3 interfered with proper development of TFR cells. Depletion of Id2 and Id3 expression in Treg cells resulted in compromised maintenance and localization of the Treg cell population. Thus, Id2 and Id3 enforce TFR cell checkpoints and control the maintenance and homing of Treg cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE57682 | GEO | 2014/06/29

SECONDARY ACCESSION(S): PRJNA247679

REPOSITORIES: GEO

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Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease

Project description:Regulatory T (Treg) cells suppress the development of inflammatory disease, but our knowledge of transcriptional regulators that control this function remains incomplete. Here we show that expression of Id2 and Id3 in Treg cells was required to suppress development of fatal inflammatory disease. We found that T cell antigen receptor (TCR)-driven signaling initially decreased the abundance of Id3, which led to the activation of a follicular regulatory T (TFR) cell–specific transcription signature. However, sustained lower abundance of Id2 and Id3 interfered with proper development of TFR cells. Depletion of Id2 and Id3 expression in Treg cells resulted in compromised maintenance and localization of the Treg cell population. Thus, Id2 and Id3 enforce TFR cell checkpoints and control the maintenance and homing of Treg cells. Treg mRNA profiles in lymph node from 3-week-old Id2fl/flId3fl/fl;Foxp3Cre/Cre (Id2 Id3 double-knockout) and control mice are generated by deep sequencing.

2014-06-29 | E-GEOD-57682 | biostudies-arrayexpress

Expression data from sorted Id3-GFP hi Id2-YFP int and Id3-GFP lo Id2-YFP hi activated CD8 T cells

Project description:During an immune response, CD8 T cells fall along a gradient of memory potential, but the regulators of these fate decsisions are not well understood. We utlized Id3-GFP and Id2-YFP reporter mice to elucidate the role of Id3 and Id2 during early CD8 T cell differentiation by gene expression. Id3-GFP hi Id2-YFP int or Id3-GFP lo Id2-YFP hi OT-I cells were sorted into trizol at day 6 of VSV-OVA infection and analyzed by microarray

2011-10-06 | E-GEOD-32675 | biostudies-arrayexpress

Expression data from sorted Id3-GFP hi Id2-YFP int and Id3-GFP lo Id2-YFP hi activated CD8 T cells

2011-10-07 | GSE32675 | GEO

A genetic circuitry linking Id-proteins (Id2 and Id3) and the AKT-FOXO-mTORC1 axis to suppress innate-variant TFH cell development, maintain T cell quiescence and prevent lymphomagenesis.

Project description:It is now well established that the E- and Id-protein axis regulates multiple steps in lymphocyte development. However, it remains unknown as to how E- and Id-proteins mechanistically enforce and maintain the naïve T cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate-variant TFH cells. Innate-variant TFH cells required MHC Class I-like signalling and were associated with germinal center B cell development. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion and activation. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities with genetic deficiencies associated with Burkitt lymphoma. We propose that in response to antigen receptor and/or cytokine signaling the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hifa and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation. RNA-seq data of 5 of wild type CD4SP cells, 3 of wild type Tfh cells, 3 of Id3-/- CD4SP cells, 3 of Id2-/-Id3-/-(dKO) CD4SP cells, and 6 of Id2-/-Id3-/- lymphoma cells.

2015-03-04 | E-GEOD-64779 | biostudies-arrayexpress

A genetic circuitry linking Id-proteins (Id2 and Id3) and the AKT-FOXO-mTORC1 axis to suppress innate-variant TFH cell development, maintain T cell quiescence and prevent lymphomagenesis.

2015-03-04 | GSE64779 | GEO

Id2-deficient NK cells acquire a naïve-like fate (Affymetrix data set)

Project description:All innate lymphoid cells (ILC) constitutively express and require the small helix-loop-helix protein ID2 but the functions of ID2 are not well understood in these cells. Here we show that natural killer (NK) cells, the prototypic ILC, can develop in the absence of ID2 but lose their innate properties and remain as CD27+CD11b- cells that fail to mature into cytotoxic effectors. We show that ID2 broadly limited chromatin accessibility at E protein binding sites near T lymphocyte-associated genes including multiple chemokine receptors, cytokine receptors, and signaling molecules. Moreover, ID2 prevented the conversion of CD27+CD11b- NK cells from a CD8 memory precursor-like chromatin accessibility state toward a naïve-like chromatin accessibility state, and altered their functional capacity. Finally, we demonstrate that increased expression of the naïve T cell-associated helix-loop-helix protein ID3 was required for development of ID2-deficient NK cells, indicating that completely unfettered E protein function is incompatible with NK cell development. These data solidify the roles of ID2 and ID3 as mediators of effector and naïve gene programs, respectively, and revealed a critical role for ID2 in promoting a chromatin state and transcriptional program in CD27+CD11b- NK cells that supports the innate properties of these cells and their ability to undergo cytotoxic effector differentiation.

2018-02-26 | GSE109456 | GEO

Id2-deficient NK cells acquire a naïve-like fate (ATAC-seq data set)

2018-02-26 | GSE109517 | GEO

Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection

Project description:T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4+ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4+CD25+FoxP3+CXCR5+PD1hiBcl-6+ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, including intermediate expression of FoxP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of TFR and both TFH and GC B-cells as well as levels of CD4+ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG or TFR within the total CD4+ T-cell pool. Finally, we examined whether higher levels of direct virus infection of TFR were responsible for their relative depletion post-SIV infection. We found that TFH, TFR and TREG sorted from SIV- infected RM harbor comparable levels of cell-associated viral DNA. Our data suggests that TFR may contribute to the regulation and proliferation of TFH and GC B-cells in vivo and that a decreased TFR/TFH ratio in chronic SIV infection may lead to unchecked expansion of both TFH and GC B-cells. TFR, TFH, TREG and bulk CD4 cells were sorted from spleens of 5 uninfected and 5 infected RM.

2015-09-02 | E-GEOD-69756 | biostudies-arrayexpress

Dynamic expression of Id3 defines the stepwise differentiation of tissue-resident regulatory T cells

Project description:Foxp3+ regulatory T (TR) cells are phenotypically and functionally diverse, and broadly distributed in lymphoid and non-lymphoid tissues. However, the pathways guiding the differentiation of tissue-resident TR populations have not been well defined. By regulating E-protein function, Id3 controls the differentiation of CD8+ effector T cells and is essential for TR maintenance and function. We show that dynamic expression of Id3 helps define three distinct mouse TR populations, Id3+CD62LhiCD44lo central (c)TR, Id3+CD62LloCD44hi effector (e)TR and Id3- eTR. Adoptive transfer experiments and transcriptome analyses support a stepwise model of differentiation from Id3+ cTR to Id3+ eTR to Id3- eTR. Furthermore, Id3- eTR have high expression of functional inhibitory markers and a transcriptional signature of tissue-resident TR. Accordingly, Id3- eTR are highly enriched in non-lymphoid organs, but virtually absent from blood and lymph. Thus, we propose that tissue-resident TR develop in a multi-step process associated with Id3 downregulation.

2018-11-16 | GSE122593 | GEO

Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection

2015-09-02 | GSE69756 | GEO

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