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

Infection, autoimmunity, and cancer are principal human health challenges of the 21 ^st 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 (T _RM ) 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 T _RM cells. Our results suggest NKG2A ⁺ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.
Competing Interests: Declaration of interests J.R.H. is a consultant for Regeneron Pharmaceuticals. J.D.G. reports contracted research, a grant, and consulting fees from Gilead. K.M.C. reports being a shareholder in Geneoscopy LLC and has received consulting fees from Geneoscopy LLC, PACT Pharma, Tango Therapeutics, Flagship Labs 81 LLC, and the Rare Cancer Research Foundation.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)