Journal Article

DZNE-2025-01134

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade.

Tsui, C. ; Heyden, L. ; Wen, L. ; Gago da Graça, C. ; Potemkin, N. ; Frolov, A.DZNE* ; Rawlinson, D. ; Qin, L. ; Wimmer, V. C. ; Hadian-Jazi, M. ; Malko, D.DZNE* ; Su, C.-H. ; Li, S. ; Wilson, K. R. ; Horvatic, H. ; Wijesinghe, S. K. ; Moreira, M. L. ; Dryburgh, L. ; Schienstock, D. ; Rausch, L. ; Utzschneider, D. T. ; Halin, C. ; Mueller, S. N. ; Beyer, M. D.DZNE* ; Bedoui, S. ; Abdullah, Z. ; Schröder, J. ; Kallies, A.

2025
Springer Nature Limited London

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Please use a persistent id in citations: doi:10.1038/s41590-025-02276-7

Abstract: Exhausted CD8+ T (TEX) cell responses are maintained by precursors of exhausted T (TPEX) cells that possess high self-renewal and developmental potential. TPEX cells also drive the proliferative burst of effector T cells upon therapeutic immune checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation and function are not well defined. Here we identify developmental and functional compartmentalization of TPEX and TEX cells across secondary lymphoid organs during chronic infection. We show that stem-like CD62L+ TPEX and effector-like CX3CR1+ TEX cells constitute a distinct developmental lineage that is promoted by the lymph node (LN) microenvironment and dependent on the transcription factor KLF2. LNs act as a niche in which migratory dendritic cells provide antigen and costimulatory signals to maintain the proliferative fitness of CD62L+ TPEX cells and generation of CX3CR1+ TEX cells. Moreover, LNs exclusively drive the proliferative burst and systemic dissemination of CX3CR1+ TEX cells during ICB. Thus, our findings identify a unique role for LNs in the maintenance of T cell differentiation and function during systemic chronic infection and ICB therapy.

Keyword(s): Animals (MeSH) ; Lymph Nodes: immunology (MeSH) ; Cell Differentiation: immunology (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; Mice (MeSH) ; Kruppel-Like Transcription Factors: metabolism (MeSH) ; Kruppel-Like Transcription Factors: genetics (MeSH) ; Kruppel-Like Transcription Factors: immunology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Immune Checkpoint Inhibitors: pharmacology (MeSH) ; CX3C Chemokine Receptor 1: metabolism (MeSH) ; Lymphocytic Choriomeningitis: immunology (MeSH) ; Lymphocytic choriomeningitis virus: immunology (MeSH) ; Persistent Infection: immunology (MeSH) ; Dendritic Cells: immunology (MeSH) ; Mice, Knockout (MeSH) ; Lymphocyte Activation: immunology (MeSH) ; Mice, Transgenic (MeSH) ; Kruppel-Like Transcription Factors ; Klf2 protein, mouse ; Immune Checkpoint Inhibitors ; CX3C Chemokine Receptor 1 ; Cx3cr1 protein, mouse

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Contributing Institute(s):

1. Immunogenomics and Neurodegeneration (AG Beyer)
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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