STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles

Jalila Alshekaili; Rochna Chand; Cindy Eunhee Lee; Susan Corley; Kristy Kwong; Ilenia Papa; David A. Fulcher; Katrina L. Randall; Jennifer W. Leiding; Cindy S. Ma; Marc R. Wilkins; Gulbu Uzel; Chris C. Goodnow; Carola G. Vinuesa; Stuart G. Tangye; Matthew C. Cook

doi:10.1038/s41598-018-21389-8

STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles

Jalila Alshekaili, Rochna Chand, Cindy Eunhee Lee, Susan Corley, Kristy Kwong, Ilenia Papa, David A. Fulcher, Katrina L. Randall, Jennifer W. Leiding, Cindy S. Ma, Marc R. Wilkins, Gulbu Uzel, Chris C. Goodnow, Carola G. Vinuesa, Stuart G. Tangye, Matthew C. Cook^*

^*Corresponding author for this work

Microbiology & Immunology

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

22 Citations (Scopus)

Abstract

A subset of human follicular helper T cells (TFH) cells expresses CD57 for which no distinct function has been identified. We show that CD57+ TFH cells are universally PD-1^hi, but compared to their CD57-PD-1^hi counterparts, express little IL-21 or IL-10 among others. Instead, CD57 expression on TFH cells marks cytotoxicity transcriptional signatures that translate into only a weak cytotoxic phenotype. Similarly, circulating PD-1+ CD57+ CD4+ T cells make less cytokine than their CD57-PD-1+ counterparts, but have a prominent cytotoxic phenotype. By analysis of responses to STAT3-dependent cytokines and cells from patients with gain-or loss-of-function STAT3 mutations, we show that CD4+ T cell cytotoxicity is STAT3-dependent. TFH formation also requires STAT3, but paradoxically, once formed, PD-1^hi cells become unresponsive to STAT3. These findings suggest that changes in blood and germinal center cytotoxicity might be affected by changes in STAT3 signaling, or modulation of PD-1 by therapy.

Original language	English
Article number	3529
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-21389-8
Publication status	Published - Dec 1 2018

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Alshekaili, J., Chand, R., Lee, C. E., Corley, S., Kwong, K., Papa, I., Fulcher, D. A., Randall, K. L., Leiding, J. W., Ma, C. S., Wilkins, M. R., Uzel, G., Goodnow, C. C., Vinuesa, C. G., Tangye, S. G., & Cook, M. C. (2018). STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles. Scientific Reports, 8(1), Article 3529. https://doi.org/10.1038/s41598-018-21389-8

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title = "STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles",

abstract = "A subset of human follicular helper T cells (TFH) cells expresses CD57 for which no distinct function has been identified. We show that CD57+ TFH cells are universally PD-1hi, but compared to their CD57-PD-1hi counterparts, express little IL-21 or IL-10 among others. Instead, CD57 expression on TFH cells marks cytotoxicity transcriptional signatures that translate into only a weak cytotoxic phenotype. Similarly, circulating PD-1+ CD57+ CD4+ T cells make less cytokine than their CD57-PD-1+ counterparts, but have a prominent cytotoxic phenotype. By analysis of responses to STAT3-dependent cytokines and cells from patients with gain-or loss-of-function STAT3 mutations, we show that CD4+ T cell cytotoxicity is STAT3-dependent. TFH formation also requires STAT3, but paradoxically, once formed, PD-1hi cells become unresponsive to STAT3. These findings suggest that changes in blood and germinal center cytotoxicity might be affected by changes in STAT3 signaling, or modulation of PD-1 by therapy.",

author = "Jalila Alshekaili and Rochna Chand and Lee, {Cindy Eunhee} and Susan Corley and Kristy Kwong and Ilenia Papa and Fulcher, {David A.} and Randall, {Katrina L.} and Leiding, {Jennifer W.} and Ma, {Cindy S.} and Wilkins, {Marc R.} and Gulbu Uzel and Goodnow, {Chris C.} and Vinuesa, {Carola G.} and Tangye, {Stuart G.} and Cook, {Matthew C.}",

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year = "2018",

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doi = "10.1038/s41598-018-21389-8",

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AU - Alshekaili, Jalila

AU - Chand, Rochna

AU - Lee, Cindy Eunhee

AU - Corley, Susan

AU - Kwong, Kristy

AU - Papa, Ilenia

AU - Fulcher, David A.

AU - Randall, Katrina L.

AU - Leiding, Jennifer W.

AU - Ma, Cindy S.

AU - Wilkins, Marc R.

AU - Uzel, Gulbu

AU - Goodnow, Chris C.

AU - Vinuesa, Carola G.

AU - Tangye, Stuart G.

AU - Cook, Matthew C.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - A subset of human follicular helper T cells (TFH) cells expresses CD57 for which no distinct function has been identified. We show that CD57+ TFH cells are universally PD-1hi, but compared to their CD57-PD-1hi counterparts, express little IL-21 or IL-10 among others. Instead, CD57 expression on TFH cells marks cytotoxicity transcriptional signatures that translate into only a weak cytotoxic phenotype. Similarly, circulating PD-1+ CD57+ CD4+ T cells make less cytokine than their CD57-PD-1+ counterparts, but have a prominent cytotoxic phenotype. By analysis of responses to STAT3-dependent cytokines and cells from patients with gain-or loss-of-function STAT3 mutations, we show that CD4+ T cell cytotoxicity is STAT3-dependent. TFH formation also requires STAT3, but paradoxically, once formed, PD-1hi cells become unresponsive to STAT3. These findings suggest that changes in blood and germinal center cytotoxicity might be affected by changes in STAT3 signaling, or modulation of PD-1 by therapy.

AB - A subset of human follicular helper T cells (TFH) cells expresses CD57 for which no distinct function has been identified. We show that CD57+ TFH cells are universally PD-1hi, but compared to their CD57-PD-1hi counterparts, express little IL-21 or IL-10 among others. Instead, CD57 expression on TFH cells marks cytotoxicity transcriptional signatures that translate into only a weak cytotoxic phenotype. Similarly, circulating PD-1+ CD57+ CD4+ T cells make less cytokine than their CD57-PD-1+ counterparts, but have a prominent cytotoxic phenotype. By analysis of responses to STAT3-dependent cytokines and cells from patients with gain-or loss-of-function STAT3 mutations, we show that CD4+ T cell cytotoxicity is STAT3-dependent. TFH formation also requires STAT3, but paradoxically, once formed, PD-1hi cells become unresponsive to STAT3. These findings suggest that changes in blood and germinal center cytotoxicity might be affected by changes in STAT3 signaling, or modulation of PD-1 by therapy.

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STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles

Abstract

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