Integrative systems biology reveals NKG2A-biased immune responses correlate with protection in infectious disease, autoimmune disease, and cancer

• Published in: Cell reports (Cambridge) Vol. 43; no. 3; p. 113872
• Main Authors: Chen, Daniel G., Xie, Jingyi, Choi, Jongchan, Ng, Rachel H., Zhang, Rongyu, Li, Sarah, Edmark, Rick, Zheng, Hong, Solomon, Ben, Campbell, Katie M., Medina, Egmidio, Ribas, Antoni, Khatri, Purvesh, Lanier, Lewis L., Mease, Philip J., Goldman, Jason D., Su, Yapeng, Heath, James R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2024; Elsevier
• Subjects: autoimmune disease; Autoimmune Diseases - pathology; Autoimmunity; cancer; CD8+ T cells; CD8-Positive T-Lymphocytes; Communicable Diseases - pathology; CP: Immunology; Humans; Immunologic Memory; infectious disease; Inflammation - pathology; multi-disease; Neoplasms - pathology; NKG2A; plasma proteomics; single-cell multi-omics; systems immunology; CP: Immunology; CD8+ T cells; plasma proteomics; infectious disease; NKG2A; single-cell multi-omics; cancer; multi-disease; autoimmune disease; systems immunology; CD8(+) T cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113872

Infection, autoimmunity, and cancer are principal human health challenges of the 21st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A+ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer. [Display omitted] •NKG2A+ bias is associated with reduced acute and post-acute COVID-19 risk•NKG2A+ bias negatively associates with inflammation from viral infection•NKG2A+ bias negatively associates with lupus•NKG2A+ bias is associated with increased survival and immune response in cancer Chen et al. show how an NKG2A+-biased immune response associates with biological and clinical correlates of protection and reduced disease severity across multiple cancers, an autoimmune disease (lupus), and multiple viral infections.