Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity

Megat H B A Hamid; Pablo F Cespedes; Chen Jin; Ji-Li Chen; Uzi Gileadi; Elie Antoun; Zhu Liang; Fei Gao; Renuka Teague; Nikita Manoharan; David Maldonado-Perez; Nasullah Khalid-Alham; Lucia Cerundolo; Raul Ciaoca; Svenja S Hester; Adán Pinto-Fernández; Simeon D Draganov; Iolanda Vendrell; Guihai Liu; Xuan Yao; Audun Kvalvaag; Delaney C C Dominey-Foy; Charunya Nanayakkara; Nikolaos Kanellakis; Yi-Ling Chen; Craig Waugh; Sally-Ann Clark; Kevin Clark; Paul Sopp; Najib M Rahman; Clare Verrill; Benedikt M Kessler; Graham Ogg; Ricardo A Fernandes; Roman Fisher; Yanchun Peng; Michael L Dustin; Tao Dong

doi:10.1038/s41590-024-01802-3

Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity

Nat Immunol. 2024 May;25(5):834-846. doi: 10.1038/s41590-024-01802-3. Epub 2024 Apr 1.

Authors

Megat H B A Hamid^#¹, Pablo F Cespedes^#^{1

2}, Chen Jin^#^{1

3}, Ji-Li Chen^#^{1

4}, Uzi Gileadi^#⁴, Elie Antoun^#^{1

5}, Zhu Liang^#^{1

6}, Fei Gao¹, Renuka Teague^{1

7}, Nikita Manoharan¹, David Maldonado-Perez^{1

7}, Nasullah Khalid-Alham^{8

9}, Lucia Cerundolo⁷, Raul Ciaoca¹, Svenja S Hester⁶, Adán Pinto-Fernández^{1

6}, Simeon D Draganov^{1

6}, Iolanda Vendrell^{1

6}, Guihai Liu¹, Xuan Yao¹, Audun Kvalvaag^{2

10}, Delaney C C Dominey-Foy¹, Charunya Nanayakkara¹, Nikolaos Kanellakis^{1

9

11

12}, Yi-Ling Chen^{1

4}, Craig Waugh¹³, Sally-Ann Clark¹³, Kevin Clark¹³, Paul Sopp¹³, Najib M Rahman^{1

9

11

12}, Clare Verrill^{1

7

9}, Benedikt M Kessler^{1

6}, Graham Ogg^{1

4}, Ricardo A Fernandes¹, Roman Fisher^{1

6}, Yanchun Peng^{1

4}, Michael L Dustin^{1

2}, Tao Dong^{14

15}

Affiliations

¹ CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
² Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
³ Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁴ MRC Translational Immune Discovery Unity, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁵ Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁶ Target Discovery Institute, Centre for Medicines Discovery, University of Oxford, Oxford, UK.
⁷ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
⁸ Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK.
⁹ Oxford National Institute of Health Research (NIHR) Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
¹⁰ Department of Molecular Cell Biology, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway.
¹¹ Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹² Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals, Oxford, UK.
¹³ Flow Cytometry Facility, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁴ CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. tao.dong@ndm.ox.ac.uk.
¹⁵ MRC Translational Immune Discovery Unity, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. tao.dong@ndm.ox.ac.uk.

^# Contributed equally.

PMID: 38561495
DOI: 10.1038/s41590-024-01802-3

Abstract

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103⁺ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61⁺ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigens, CD* / immunology
Antigens, CD* / metabolism
Apyrase*
Cell Line, Tumor
Cytotoxicity, Immunologic
Humans
Integrin alpha Chains* / metabolism
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Mice
Neoplasms / immunology
Neoplasms / therapy
Receptors, Antigen, T-Cell* / immunology
Receptors, Antigen, T-Cell* / metabolism
Signal Transduction* / immunology
T-Lymphocytes, Cytotoxic / immunology

Substances

alpha E integrins
Antigens, CD
Integrin alpha Chains
Receptors, Antigen, T-Cell
ENTPD1 protein, human
Apyrase

Grants and funding

2018-I2M-002/Chinese Academy of Medical Sciences (CAMS)