Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function

Jayati Basu; Bernardo S. Reis; Suraj Peri; Jikun Zha; Xiang Hua; Lu Ge; Kyle Ferchen; Emmanuelle Nicolas; Philip Czyzewicz; Kathy Q. Cai; Yinfei Tan; Juan I. Fuxman Bass; Albertha J.M. Walhout; H. Leighton Grimes; Sergei I. Grivennikov; Daniel Mucida; Dietmar J. Kappes

doi:10.1038/s41590-021-00980-8

Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4⁺ T cell identity and function

Jayati Basu, Bernardo S. Reis, Suraj Peri, Jikun Zha, Xiang Hua, Lu Ge, Kyle Ferchen, Emmanuelle Nicolas, Philip Czyzewicz, Kathy Q. Cai, Yinfei Tan, Juan I. Fuxman Bass, Albertha J.M. Walhout, H. Leighton Grimes, Sergei I. Grivennikov, Daniel Mucida, Dietmar J. Kappes

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4⁺ intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (Sil^ThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the Sil^ThPOK to maintain its own long-term expression in CD4 T cells. Disruption of this loop in vivo prevents persistent ThPOK expression, leads to genome-wide changes in chromatin accessibility and derepresses the colonic regulatory T (T_reg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITR^loPD-1^loCD25^lo (Triple^lo) T_reg cells and conversion to CD4⁺ IELs in the gut, thereby providing dominant protection from colitis. Hence, the ThPOK autoregulatory loop represents a key mechanism to physiologically control ThPOK expression and T cell differentiation in the gut, with potential therapeutic relevance.

Original language	English
Pages (from-to)	969-982
Number of pages	14
Journal	Nature Immunology
Volume	22
Issue number	8
DOIs	https://doi.org/10.1038/s41590-021-00980-8
State	Published - Jul 2021

Keywords

Animals
Cell Differentiation/immunology
Colitis/immunology
DNA-Binding Proteins/genetics
Disease Models, Animal
Female
Intestinal Mucosa/cytology
Intraepithelial Lymphocytes/cytology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
T-Lymphocytes, Helper-Inducer/cytology
T-Lymphocytes, Regulatory/cytology
Transcription Factors/genetics
Transcription, Genetic/genetics

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10.1038/s41590-021-00980-8

Cite this

Basu, J., Reis, B. S., Peri, S., Zha, J., Hua, X., Ge, L., Ferchen, K., Nicolas, E., Czyzewicz, P., Cai, K. Q., Tan, Y., Fuxman Bass, J. I., Walhout, A. J. M., Grimes, H. L., Grivennikov, S. I., Mucida, D., & Kappes, D. J. (2021). Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4⁺ T cell identity and function. Nature Immunology, 22(8), 969-982. https://doi.org/10.1038/s41590-021-00980-8

@article{efef57c9e81047299c688f119df76d88,

title = "Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function",

abstract = "The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4+ intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (SilThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the SilThPOK to maintain its own long-term expression in CD4 T cells. Disruption of this loop in vivo prevents persistent ThPOK expression, leads to genome-wide changes in chromatin accessibility and derepresses the colonic regulatory T (Treg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITRloPD-1loCD25lo (Triplelo) Treg cells and conversion to CD4+ IELs in the gut, thereby providing dominant protection from colitis. Hence, the ThPOK autoregulatory loop represents a key mechanism to physiologically control ThPOK expression and T cell differentiation in the gut, with potential therapeutic relevance.",

keywords = "Animals, Cell Differentiation/immunology, Colitis/immunology, DNA-Binding Proteins/genetics, Disease Models, Animal, Female, Intestinal Mucosa/cytology, Intraepithelial Lymphocytes/cytology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Helper-Inducer/cytology, T-Lymphocytes, Regulatory/cytology, Transcription Factors/genetics, Transcription, Genetic/genetics",

author = "Jayati Basu and Reis, {Bernardo S.} and Suraj Peri and Jikun Zha and Xiang Hua and Lu Ge and Kyle Ferchen and Emmanuelle Nicolas and Philip Czyzewicz and Cai, {Kathy Q.} and Yinfei Tan and {Fuxman Bass}, {Juan I.} and Walhout, {Albertha J.M.} and Grimes, {H. Leighton} and Grivennikov, {Sergei I.} and Daniel Mucida and Kappes, {Dietmar J.}",

note = "{\textcopyright} 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = jul,

doi = "10.1038/s41590-021-00980-8",

language = "English",

volume = "22",

pages = "969--982",

journal = "Nature Immunology",

issn = "1529-2908",

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Basu, J, Reis, BS, Peri, S, Zha, J, Hua, X, Ge, L, Ferchen, K, Nicolas, E, Czyzewicz, P, Cai, KQ, Tan, Y, Fuxman Bass, JI, Walhout, AJM, Grimes, HL, Grivennikov, SI, Mucida, D & Kappes, DJ 2021, 'Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4⁺ T cell identity and function', Nature Immunology, vol. 22, no. 8, pp. 969-982. https://doi.org/10.1038/s41590-021-00980-8

TY - JOUR

T1 - Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function

AU - Basu, Jayati

AU - Reis, Bernardo S.

AU - Peri, Suraj

AU - Zha, Jikun

AU - Hua, Xiang

AU - Ge, Lu

AU - Ferchen, Kyle

AU - Nicolas, Emmanuelle

AU - Czyzewicz, Philip

AU - Cai, Kathy Q.

AU - Tan, Yinfei

AU - Fuxman Bass, Juan I.

AU - Walhout, Albertha J.M.

AU - Grimes, H. Leighton

AU - Grivennikov, Sergei I.

AU - Mucida, Daniel

AU - Kappes, Dietmar J.

PY - 2021/7

Y1 - 2021/7

N2 - The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4+ intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (SilThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the SilThPOK to maintain its own long-term expression in CD4 T cells. Disruption of this loop in vivo prevents persistent ThPOK expression, leads to genome-wide changes in chromatin accessibility and derepresses the colonic regulatory T (Treg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITRloPD-1loCD25lo (Triplelo) Treg cells and conversion to CD4+ IELs in the gut, thereby providing dominant protection from colitis. Hence, the ThPOK autoregulatory loop represents a key mechanism to physiologically control ThPOK expression and T cell differentiation in the gut, with potential therapeutic relevance.

AB - The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4+ intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (SilThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the SilThPOK to maintain its own long-term expression in CD4 T cells. Disruption of this loop in vivo prevents persistent ThPOK expression, leads to genome-wide changes in chromatin accessibility and derepresses the colonic regulatory T (Treg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITRloPD-1loCD25lo (Triplelo) Treg cells and conversion to CD4+ IELs in the gut, thereby providing dominant protection from colitis. Hence, the ThPOK autoregulatory loop represents a key mechanism to physiologically control ThPOK expression and T cell differentiation in the gut, with potential therapeutic relevance.

KW - Animals

KW - Cell Differentiation/immunology

KW - Colitis/immunology

KW - DNA-Binding Proteins/genetics

KW - Disease Models, Animal

KW - Female

KW - Intestinal Mucosa/cytology

KW - Intraepithelial Lymphocytes/cytology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - T-Lymphocytes, Helper-Inducer/cytology

KW - T-Lymphocytes, Regulatory/cytology

KW - Transcription Factors/genetics

KW - Transcription, Genetic/genetics

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U2 - 10.1038/s41590-021-00980-8

DO - 10.1038/s41590-021-00980-8

M3 - Article

C2 - 34312548

SN - 1529-2908

VL - 22

SP - 969

EP - 982

JO - Nature Immunology

JF - Nature Immunology

IS - 8

ER -

Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4⁺ T cell identity and function

Abstract

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Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function

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Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4⁺ T cell identity and function