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Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.

Frank A Buquicchio1, Raissa Fonseca2, Patrick K Yan3

  • 1Department of Pathology, Stanford University, Stanford, CA 94305, USA; Program in Immunology, Stanford University, Stanford, CA 94304, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.

Immunity
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Summary

Tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells exhibit distinct epigenetic landscapes. This study reveals key regulators and epigenetic signatures defining TRM cell development and function across organs.

Keywords:
chromatin accessibilitydevelopmentepigeneticsregulatory elementssingle-cell genomicstissue immunitytissue-resident memory T cellstranscriptional regulators

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Area of Science:

  • Immunology
  • Epigenetics
  • Cell Biology

Background:

  • Memory CD8+ T cell pool comprises heterogeneous subsets with specialized functions.
  • Understanding the epigenetic basis of tissue-resident memory T (TRM) cell heterogeneity is crucial.

Purpose of the Study:

  • To investigate the epigenetic landscape of memory CD8+ T cells in various non-lymphoid organs and circulation.
  • To identify regulators and epigenetic signatures of tissue-resident memory T (TRM) cell development.
  • To compare epigenetic states of TRM cells, circulating memory T (TCIRC) cells, and exhausted T (TEX) cells.

Main Methods:

  • Single-cell transposase-accessible chromatin sequencing (scATAC-seq) applied to CD8+ T cells from seven non-lymphoid organs and circulation.
  • Analysis of epigenetic landscapes across four distinct infection models.
  • Identification of transcriptional regulators and epigenetic signatures.

Main Results:

  • Tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells follow distinct epigenetic trajectories.
  • Organ-specific transcriptional regulators (FOSB, FOS, FOSL1, BACH2) and a common TRM epigenetic signature were identified.
  • Terminal exhausted T (TEX) cells possess unique epigenetic features distinct from TRM cells.

Conclusions:

  • Epigenetic reprogramming drives the development of distinct tissue-adapted memory CD8+ T cell states.
  • Chromatin accessibility changes are critical for defining TRM cell specialization and function.
  • This study provides a comprehensive epigenetic resource for understanding memory T cell heterogeneity.