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

Sci Rep. 2018 Feb 23;8(1):3529. doi: 10.1038/s41598-018-21389-8.

Authors

Jalila Alshekaili^{1

2

3

4}, Rochna Chand^{1

2}, Cindy Eunhee Lee^{1

2}, Susan Corley⁵, Kristy Kwong^{1

2}, Ilenia Papa¹, David A Fulcher¹, Katrina L Randall^{1

3}, Jennifer W Leiding⁶, Cindy S Ma^{7

8}, Marc R Wilkins⁵, Gulbu Uzel⁹, Chris C Goodnow^{1

7

8}, Carola G Vinuesa¹, Stuart G Tangye^{7

8}, Matthew C Cook^{10

11

12}

Affiliations

¹ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, ACT, 2601, Australia.
² Translational Research Unit, Level 6 Building 10, Canberra Hospital, Woden, ACT, 2606, Australia.
³ Department of Immunology, Canberra Hospital, Woden, ACT, 2606, Australia.
⁴ Department of Microbiology and Immunology, Sultan Qaboos University Hospital, Seeb, Oman.
⁵ Systems Biology Initiative, School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, Australia.
⁶ Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of South Florida and Johns Hopskins All Children's Hospital, St Petersburg, Florida, USA.
⁷ Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
⁸ St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, 2010, Australia.
⁹ Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹⁰ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, ACT, 2601, Australia. matthew.cook@anu.edu.au.
¹¹ Translational Research Unit, Level 6 Building 10, Canberra Hospital, Woden, ACT, 2606, Australia. matthew.cook@anu.edu.au.
¹² Department of Immunology, Canberra Hospital, Woden, ACT, 2606, Australia. matthew.cook@anu.edu.au.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD57 Antigens / genetics
CD57 Antigens / immunology*
Case-Control Studies
Cell Proliferation
Cytotoxicity, Immunologic
Gene Expression Regulation / immunology*
Humans
Immunophenotyping
Interleukin-10 / genetics
Interleukin-10 / immunology
Interleukins / genetics
Interleukins / immunology
Palatine Tonsil / immunology
Palatine Tonsil / pathology
Palatine Tonsil / surgery
Phenotype
Primary Cell Culture
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / immunology*
Signal Transduction
T-Lymphocytes, Cytotoxic / immunology*
T-Lymphocytes, Cytotoxic / pathology
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Helper-Inducer / pathology
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / pathology
Tonsillectomy
Tonsillitis / genetics
Tonsillitis / immunology*
Tonsillitis / pathology
Tonsillitis / surgery

Substances

CD57 Antigens
IL10 protein, human
Interleukins
PDCD1 protein, human
Programmed Cell Death 1 Receptor
STAT3 Transcription Factor
STAT3 protein, human
Interleukin-10
interleukin-21