TY  - JOUR
AU  - Tsui, Carlson
AU  - Heyden, Leonie
AU  - Wen, Lifen
AU  - Gago da Graça, Catarina
AU  - Potemkin, Nikita
AU  - Frolov, Aleksej
AU  - Rawlinson, Daniel
AU  - Qin, Lei
AU  - Wimmer, Verena C
AU  - Hadian-Jazi, Marjan
AU  - Malko, Darya
AU  - Su, Chun-Hsi
AU  - Li, Sining
AU  - Wilson, Kayla R
AU  - Horvatic, Helena
AU  - Wijesinghe, Sharanya K
AU  - Moreira, Marcela L
AU  - Dryburgh, Lachlan
AU  - Schienstock, Dominik
AU  - Rausch, Lisa
AU  - Utzschneider, Daniel T
AU  - Halin, Cornelia
AU  - Mueller, Scott N
AU  - Beyer, Marc D
AU  - Bedoui, Sammy
AU  - Abdullah, Zeinab
AU  - Schröder, Jan
AU  - Kallies, Axel
TI  - Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade.
JO  - Nature immunology
VL  - 26
IS  - 10
SN  - 1529-2908
CY  - London
PB  - Springer Nature Limited
M1  - DZNE-2025-01134
SP  - 1752 - 1765
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Lymph Nodes: immunology
KW  - Cell Differentiation: immunology
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - Mice
KW  - Kruppel-Like Transcription Factors: metabolism
KW  - Kruppel-Like Transcription Factors: genetics
KW  - Kruppel-Like Transcription Factors: immunology
KW  - Mice, Inbred C57BL
KW  - Immune Checkpoint Inhibitors: pharmacology
KW  - CX3C Chemokine Receptor 1: metabolism
KW  - Lymphocytic Choriomeningitis: immunology
KW  - Lymphocytic choriomeningitis virus: immunology
KW  - Persistent Infection: immunology
KW  - Dendritic Cells: immunology
KW  - Mice, Knockout
KW  - Lymphocyte Activation: immunology
KW  - Mice, Transgenic
KW  - Kruppel-Like Transcription Factors (NLM Chemicals)
KW  - Klf2 protein, mouse (NLM Chemicals)
KW  - Immune Checkpoint Inhibitors (NLM Chemicals)
KW  - CX3C Chemokine Receptor 1 (NLM Chemicals)
KW  - Cx3cr1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40954251
DO  - DOI:10.1038/s41590-025-02276-7
UR  - https://pub.dzne.de/record/281515
ER  -