Functional delineation of tissue-resident CD8 T cell heterogeneity during infection and cancer

• Published in: bioRxiv
• Main Authors: Milner, J Justin, Toma, Clara, He, Zhaoren, Kurd, Nadia S, Nguyen, Quynh P, Mcdonald, Bryan, Quezada, Lauren, Widjaja, Christella E, Witherden, Deborah A, Crowl, John T, Yeo, Gene W, Chang, John T, Omilusik, Kyla D, Goldrath, Ananda W
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 06.03.2020
• Subjects: Bacterial infections; CD8 antigen; Epithelium; Immunological memory; Infections; Lymphocytes; Lymphocytes T; Lymphoid tissue; Malignancy; Memory cells; Small intestine; Tumor-infiltrating lymphocytes
• DOI: 10.1101/2020.03.05.979146

Unremitting defense against diverse pathogens and malignancies requires a dynamic and durable immune response. Tissue-resident memory CD8 T cells (Trm) afford robust protection against infection and cancer progression through continuous surveillance of non-lymphoid tissues. Here, we provide insight into how Trm confer potent and persistent immunity through partitioning of distinct cellular subsets differing in longevity, effector function, and multipotency. Antigen-specific CD8 T cells localized to the epithelium of the small intestine are primarily comprised of a shorter-lived effector population most prominent early following both acute viral and bacterial infections, and a longer-lived Id3hi Trm population that subsequently accumulates at later memory timepoints. We define regulatory gene-programs driving these distinct Trm states, and further clarify roles for Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trm heterogeneity during infection. Further, through single-cell RNAseq analysis we demonstrate that tumor-infiltrating lymphocytes broadly differentiate into discrete populations of short-lived and long-lived Trm-like subsets, which share qualities with terminally-exhausted and progenitor-exhausted cells, respectively. As the clinical relevance of Trm continues to widen from acute infections to settings of chronic inflammation and malignancy, clarification of the spectrum of phenotypic and functional states exhibited by CD8 T cells that reside in non-lymphoid tissues will provide a framework for understanding their regulation and identity in diverse pathophysiological contexts.