HLA class I signal peptide variation predicts strength of NKG2A⁺ NK cell response to missing-self and risk of human disease

Zhansong Lin^#^{1

2}, Arman A Bashirova^#^{1

2}, Cian Callahan², George W Nelson^{1

2}, Emma Robinson^{1

2}, Mathias Viard^{1

2}, Minzhong Tang³, Allan Hildesheim⁴, Andre Franke⁵, John D Rioux⁶, Wilfredo Garcia-Beltran^{7

8}, Mary Carrington^{9

10

11}

Affiliations

¹ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.
² Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
³ Key Laboratory of Nasopharyngeal Carcinoma Molecular Epidemiology, Wuzhou Red Cross Hospital, Wuzhou, China.
⁴ Agencia Costarricense de Investigaciones Biomedicas, San Jose, Costa Rica.
⁵ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
⁶ Montreal Heart Institute Research Centre, Université de Montréal, Montreal, Quebec, Canada.
⁷ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
⁹ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA. carringm@mail.nih.gov.
¹⁰ Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. carringm@mail.nih.gov.
¹¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. carringm@mail.nih.gov.

^# Contributed equally.

PMID: 41781709
DOI: 10.1038/s41590-026-02436-3

HLA class I signal peptide variation predicts strength of NKG2A⁺ NK cell response to missing-self and risk of human disease

Zhansong Lin et al. Nat Immunol. 2026.

. 2026 Mar 4.

doi: 10.1038/s41590-026-02436-3. Online ahead of print.

Authors

Affiliations

¹ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.
² Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
³ Key Laboratory of Nasopharyngeal Carcinoma Molecular Epidemiology, Wuzhou Red Cross Hospital, Wuzhou, China.
⁴ Agencia Costarricense de Investigaciones Biomedicas, San Jose, Costa Rica.
⁵ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
⁶ Montreal Heart Institute Research Centre, Université de Montréal, Montreal, Quebec, Canada.
⁷ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
⁹ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA. carringm@mail.nih.gov.
¹⁰ Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. carringm@mail.nih.gov.
¹¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. carringm@mail.nih.gov.

^# Contributed equally.

PMID: 41781709
DOI: 10.1038/s41590-026-02436-3

Abstract

Natural killer (NK) cells expressing inhibitory receptors that recognize self human leukocyte antigen (HLA) class I molecules gain enhanced functionality-a process influenced by genetic polymorphism that dictates the strength of interactions between inhibitory receptors and their HLA ligands. Inhibitory CD94/NKG2A binds HLA-E loaded with epitopes derived from polymorphic HLA class I signal peptides (SPs). We generated a metric, called SP score, that quantifies the overall strength of CD94/NKG2A-HLA-E interactions based on a person's SP genotype. SP scores correlated positively with NKG2A⁺CD56^bright NK cell response to HLA class I-negative cells, indicating that CD94/NKG2A-HLA-E interaction strength promotes NK cell education. Concordantly, higher SP scores associated with lower risk of nasopharyngeal carcinoma and ulcerative colitis. Thus, the SP score may serve as a genetic tool to guide clinical NK cell intervention strategies, including therapeutic NKG2A blockade.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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HLA class I signal peptide variation predicts strength of NKG2A⁺ NK cell response to missing-self and risk of human disease

Affiliations

HLA class I signal peptide variation predicts strength of NKG2A⁺ NK cell response to missing-self and risk of human disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources

Research Materials