What Happens in the Thymus Does Not Stay in the Thymus: How T Cells Recycle the CD4+–CD8+ Lineage Commitment Transcriptional Circuitry To Control Their Function

The CD4+-lineage specific transcription factor Thpok is required for intrathymic CD4+ T cell differentiation and, together with its homolog LRF, supports CD4+ T cell helper effector responses. However, it is not known if these factors are needed for the T regulatory (Treg) arm of MHC-II responses. Here, by inactivating in mice the genes encoding both factors in differentiated Tregs, we show that Thpok and LRF are redundantly required to maintain the size and functions of the post-thymic Treg pool. They support IL 2-mediated gene expression and the functions of the Treg-specific factor Foxp3. Accordingly, Treg-specific disruption of Thpok and Lrf causes a lethal inflammatory syndrome similar to that resulting from Treg deficiency. Unlike in conventional T cells, Thpok and LRF functions in Tregs are not mediated by their repression of the transcription factor Runx3. Additionally, we found Thpok needed for the differentiation of thymic Treg precursors, an observation in line with the fact that Foxp3+ Tregs are CD4+ cells. Thus, a common Thpok-LRF node supports both helper and regulatory arms of MHC-II responses.

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“…2H). Thus, Thpok and LRF redundantly support the CD4 + CD8 − expression pattern of Tregs, as they do for conventional CD4 + T cells (16, 42). …”

Section: Resultsmentioning

confidence: 80%

“…In thymocytes and conventional T cells, Thpok acts by inhibiting the expression and function of the transcription factor Runx3 (16, 39, 42). dKO Tregs had increased levels of Runx3, but not of its homolog Runx1 which is expressed in wild-type Tregs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

Carpenter

Wohlfert

Chopp

et al. 2017

The Journal of Immunology

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“…In contrast to Tc17 CD8 + T cells, in which inhibition of cytotoxic gene expression relies on the STAT3-driven T eff 17 circuitry, both that circuitry and the CD4 + lineage-specific transcription factor Thpok contribute to restrain cytotoxic genes in Th17 CD4 + T cells. Of note, Thpok-mediated repression of IFNγ can be overcome by Th1-inducing environmental cues, despite persistent Thpok expression (28,29,58). Accordingly, Th17 effectors, which harbor epigenetic marks of activity at Th1 loci, can acquire IFNγ production and contribute to immunopathology during inflammation (59,60).…”

Section: Discussionmentioning

confidence: 99%

A STAT3-dependent transcriptional circuitry inhibits cytotoxic gene expression in T cells

Ciucci

Vacchio

Bosselut

2017

Proc. Natl. Acad. Sci. U.S.A.

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CD8 T cells are preprogrammed for cytotoxic differentiation in the thymus as they acquire expression of the transcription factor Runx3. However, a subset of effector CD8 T cells (Tc17) produce IL-17 and fail to express cytotoxic genes. Here, we show that the transcription factors directing IL-17 production, STAT3 and RORγt, inhibit cytotoxicity despite persistent Runx3 expression. Cytotoxic gene repression did not require the transcription factor Thpok, which in CD4 T cells restrains Runx3 functions and cytotoxicity; and STAT3 restrained cytotoxic gene expression in CD8 T cells responding to viral infection in vivo. STAT3-induced RORγt represses cytotoxic genes by inhibiting the functions but not the expression of the "cytotoxic" transcription factors T-bet and Eomesodermin. Thus, the transcriptional circuitry directing IL-17 expression inhibits cytotoxic functions. However, by allowing expression of activators of the cytotoxic program, this inhibitory mechanism contributes to the instability of IL-17-producing T cells.

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“…The thymic differentiation of helper CD4 and cytotoxic CD8 T lymphocytes results from the opposite activity of key transcription factors (TF) including ThPOK and Runx3 repressing the expression of CD8 and CD4 T cell lineage genes, respectively. After emigration from the thymus, naive CD8 and CD4 T cells maintain the expression of Runx3 or ThPOK, respectively, suggesting that the lineage-defining role of these TF is also active in the periphery ( Vacchio and Bosselut, 2016 ). However, the repression of a cytotoxic program in peripheral CD4 T cells is not absolute as these cells can acquire perforin-dependent cytotoxic activity ( Appay et al, 2002a ; van de Berg et al, 2008 ; Cheroutre and Husain, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes

Serroukh

Gu-Trantien

Kashani

et al. 2018

eLife

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Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer.

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What Happens in the Thymus Does Not Stay in the Thymus: How T Cells Recycle the CD4+–CD8+ Lineage Commitment Transcriptional Circuitry To Control Their Function

Cited by 28 publications

References 111 publications

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

A STAT3-dependent transcriptional circuitry inhibits cytotoxic gene expression in T cells

The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes

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