Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8 + T cells underlies distinct functional potential
Year: 2025
Type: preprint
Abstract: Persistent antigen stimulation promotes differentiation of exhausted CD8 + T (T EX ) cells. T EX cells are distinct from circulating memory T (T CIRCM ) cells but share many features with tissue-resident memory (T RM ) cells established following infection resolution. CD8 + T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional T RM or T EX cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident T EX (TR-T EX ) cells that are ontologically and functionally distinct from T RM cells generated after antigen clearance. TR-T EX phenotypically resembled T RM cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although T EX progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional T RM cells after antigen withdrawal. Conversely, T RM cells were able to differentiate into T EX cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-T EX cells with patient responses to immune checkpoint blockade, and only TR-T EX but not T RM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T EX and T RM cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.
Authors: Simone L. Park, Mark M. Painter, Sasikanth Manne, Victor Alcalde, Maura McLaughlin, Matthew A. Sullivan, Divij Mathew, Leonel Torres, Yinghui J. Huang, David B. Reeg, Naomi R. Douek, Trenton Campos, Max Klapholz, Maria A. Cardenas, Victoria Fang, Shin Foong Ngiow, KC Wumesh, Rishi R. Goel, Amy E. Baxter, Jennifer E. Wu, Melody Tan, Corbett T. Berry, Christoph T. Ellebrecht, Alexander C. Huang, Emily Papazian, Ying Liu, Karthik Rajasekaran, Robert M. Brody, Erica R. Thaler, Devraj Basu, Ahmed Diab, Josephine R. Giles, E. John Wherry
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Testing the role of BATF as a pioneer transcription factor in effector T cells, Training Program/Rheumatic Diseases, Exploiting differences in HPV oncoprotein function among oropharyngeal cancers to personalize therapy, Engineering T cells to Provide Durable Control of HIV-1 Replication, Temporal control of differentiation and epigenetics of Exhausted CD8 T cells by Tox, Elucidating the lineage dynamics of optimal human CD8 T cell responses to SARS-CoV-2 and how CD8 T cell homeostasis is altered in Long COVID, Molecular Mechanisms of TOX-mediated Programming of CD8 T Cell Exhaustion, Durable Alteration of the Human Immune system after Infection or Immunotherapy, Role of progenitor exhausted CD8 T cells and the progenitor niche in anti-PD1 efficacy, Synergies among inhibitory receptors in tolerance and disease, Penn Skin Biology and Diseases Resource-based Center, SPORE in Skin Cancer, Penn Dermatology Research Training Program, Radiation and checkpoint blockade for cancer immune therapy
OpenAlex ID: W4413168023