Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells

Marc Rigau; Simone Ostrouska; Thomas S Fulford; Darryl N Johnson; Katherine Woods; Zheng Ruan; Hamish E G McWilliam; Christopher Hudson; Candani Tutuka; Adam K Wheatley; Stephen J Kent; Jose A Villadangos; Bhupinder Pal; Christian Kurts; Jason Simmonds; Matthias Pelzing; Andrew D Nash; Andrew Hammet; Anne M Verhagen; Gino Vairo; Eugene Maraskovsky; Con Panousis; Nicholas A Gherardin; Jonathan Cebon; Dale I Godfrey; Andreas Behren; Adam P Uldrich

doi:10.1126/science.aay5516

Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells

Science. 2020 Feb 7;367(6478):eaay5516. doi: 10.1126/science.aay5516. Epub 2020 Jan 9.

Authors

Marc Rigau^{1

2

3}, Simone Ostrouska^{4

5}, Thomas S Fulford¹, Darryl N Johnson^{1

3}, Katherine Woods^{4

5

6}, Zheng Ruan^{1

3}, Hamish E G McWilliam^{1

7}, Christopher Hudson⁶, Candani Tutuka^{4

5}, Adam K Wheatley^{1

8}, Stephen J Kent^{1

8}, Jose A Villadangos^{1

7}, Bhupinder Pal^{4

5}, Christian Kurts², Jason Simmonds⁹, Matthias Pelzing⁹, Andrew D Nash⁹, Andrew Hammet⁹, Anne M Verhagen⁹, Gino Vairo⁹, Eugene Maraskovsky⁹, Con Panousis⁹, Nicholas A Gherardin¹, Jonathan Cebon^{4

5

6

10

11}, Dale I Godfrey^#^{12

3}, Andreas Behren^#^{13

5

6

10}, Adam P Uldrich^#^{12

3}

Affiliations

¹ Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia.
² University of Bonn, Bonn, Germany.
³ Australian Research Council Centre of Excellence for Advanced Molecular Imaging at the University of Melbourne, Victoria 3010, Australia.
⁴ Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia.
⁵ School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
⁶ Ludwig Institute for Cancer Research, Melbourne -Austin Branch, Victoria 3084, Australia.
⁷ Department of Biochemistry and Molecular Biology at the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
⁸ Australian Research Council Centre of Excellence for Convergent Bio-Nano Science and Technology at the University of Melbourne, Victoria 3010, Australia.
⁹ CSL Limited at the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
¹⁰ Department of Medicine, The University of Melbourne, Melbourne, Victoria 3010, Australia.
¹¹ Austin Health, Heidelberg, Victoria 3084, Australia.
¹² Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia. [email protected] [email protected] [email protected].
¹³ Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia. [email protected] [email protected] [email protected].

^# Contributed equally.

PMID: 31919129
DOI: 10.1126/science.aay5516

Abstract

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2⁺ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9⁺ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell-based immunotherapies.

Publication types

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

MeSH terms

Antigens, CD / chemistry
Antigens, CD / immunology
Antigens, Neoplasm / immunology*
Butyrophilins / chemistry
Butyrophilins / genetics
Butyrophilins / immunology*
Cell Line, Tumor
Humans
Ligands
Lymphocyte Activation
Phosphorylation
Protein Domains
Protein Multimerization
Receptors, Antigen, T-Cell, gamma-delta / immunology*
T-Lymphocytes / immunology*

Substances

Antigens, CD
Antigens, Neoplasm
BTN2A1 protein, human
BTN3A1 protein, human
Butyrophilins
Ligands
Receptors, Antigen, T-Cell, gamma-delta
T-cell receptor Vdelta2, human
T-cell receptor Vgamma9, human

Grants and funding

Australian Research Council/International