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000281515 0247_ $$2doi$$a10.1038/s41590-025-02276-7
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000281515 037__ $$aDZNE-2025-01134
000281515 041__ $$aEnglish
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000281515 1001_ $$00000-0003-0642-814X$$aTsui, Carlson$$b0
000281515 245__ $$aLymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade.
000281515 260__ $$aLondon$$bSpringer Nature Limited$$c2025
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000281515 520__ $$aExhausted 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.
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000281515 650_7 $$2NLM Chemicals$$aKruppel-Like Transcription Factors
000281515 650_7 $$2NLM Chemicals$$aKlf2 protein, mouse
000281515 650_7 $$2NLM Chemicals$$aImmune Checkpoint Inhibitors
000281515 650_7 $$2NLM Chemicals$$aCX3C Chemokine Receptor 1
000281515 650_7 $$2NLM Chemicals$$aCx3cr1 protein, mouse
000281515 650_2 $$2MeSH$$aAnimals
000281515 650_2 $$2MeSH$$aLymph Nodes: immunology
000281515 650_2 $$2MeSH$$aCell Differentiation: immunology
000281515 650_2 $$2MeSH$$aCD8-Positive T-Lymphocytes: immunology
000281515 650_2 $$2MeSH$$aMice
000281515 650_2 $$2MeSH$$aKruppel-Like Transcription Factors: metabolism
000281515 650_2 $$2MeSH$$aKruppel-Like Transcription Factors: genetics
000281515 650_2 $$2MeSH$$aKruppel-Like Transcription Factors: immunology
000281515 650_2 $$2MeSH$$aMice, Inbred C57BL
000281515 650_2 $$2MeSH$$aImmune Checkpoint Inhibitors: pharmacology
000281515 650_2 $$2MeSH$$aCX3C Chemokine Receptor 1: metabolism
000281515 650_2 $$2MeSH$$aLymphocytic Choriomeningitis: immunology
000281515 650_2 $$2MeSH$$aLymphocytic choriomeningitis virus: immunology
000281515 650_2 $$2MeSH$$aPersistent Infection: immunology
000281515 650_2 $$2MeSH$$aDendritic Cells: immunology
000281515 650_2 $$2MeSH$$aMice, Knockout
000281515 650_2 $$2MeSH$$aLymphocyte Activation: immunology
000281515 650_2 $$2MeSH$$aMice, Transgenic
000281515 693__ $$0EXP:(DE-2719)PRECISE-20190321$$5EXP:(DE-2719)PRECISE-20190321$$ePlatform for Single Cell Genomics and Epigenomics at DZNE  University of Bonn$$x0
000281515 7001_ $$00009-0001-2018-8747$$aHeyden, Leonie$$b1
000281515 7001_ $$00000-0003-0229-7306$$aWen, Lifen$$b2
000281515 7001_ $$aGago da Graça, Catarina$$b3
000281515 7001_ $$aPotemkin, Nikita$$b4
000281515 7001_ $$0P:(DE-2719)9002087$$aFrolov, Aleksej$$b5
000281515 7001_ $$00000-0002-3122-6243$$aRawlinson, Daniel$$b6
000281515 7001_ $$00009-0004-0572-0338$$aQin, Lei$$b7
000281515 7001_ $$aWimmer, Verena C$$b8
000281515 7001_ $$00000-0002-1948-7491$$aHadian-Jazi, Marjan$$b9
000281515 7001_ $$0P:(DE-2719)2814800$$aMalko, Darya$$b10
000281515 7001_ $$aSu, Chun-Hsi$$b11
000281515 7001_ $$00009-0001-4847-7153$$aLi, Sining$$b12
000281515 7001_ $$00000-0003-2023-7964$$aWilson, Kayla R$$b13
000281515 7001_ $$00000-0002-4188-4039$$aHorvatic, Helena$$b14
000281515 7001_ $$aWijesinghe, Sharanya K$$b15
000281515 7001_ $$00000-0003-3477-0727$$aMoreira, Marcela L$$b16
000281515 7001_ $$00009-0007-5579-7466$$aDryburgh, Lachlan$$b17
000281515 7001_ $$00000-0001-8440-0009$$aSchienstock, Dominik$$b18
000281515 7001_ $$aRausch, Lisa$$b19
000281515 7001_ $$00000-0003-2205-9057$$aUtzschneider, Daniel T$$b20
000281515 7001_ $$00000-0002-7899-2850$$aHalin, Cornelia$$b21
000281515 7001_ $$00000-0002-3838-3989$$aMueller, Scott N$$b22
000281515 7001_ $$0P:(DE-2719)2812219$$aBeyer, Marc D$$b23
000281515 7001_ $$00000-0002-7443-0543$$aBedoui, Sammy$$b24
000281515 7001_ $$aAbdullah, Zeinab$$b25
000281515 7001_ $$aSchröder, Jan$$b26
000281515 7001_ $$00000-0002-6312-6968$$aKallies, Axel$$b27
000281515 773__ $$0PERI:(DE-600)2026412-4$$a10.1038/s41590-025-02276-7$$gVol. 26, no. 10, p. 1752 - 1765$$n10$$p1752 - 1765$$tNature immunology$$v26$$x1529-2908$$y2025
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