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KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3

ABSTRACT: Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating versus tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency versus recirculation, or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8+ T cell activation leads to rapid transcriptional reprograming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (TRM). Klf2-deficient memory CD8+ T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest KLF2 diverts CD8+ T cells from the TRM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of TRM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate KLFs occupy a central nexus in coordinating activated CD8+ T cell differentiation and trafficking.

ORGANISM(S): Mus musculus

PROVIDER: GSE322657 | GEO | 2026/03/10

REPOSITORIES: GEO

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KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3

Project description:Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating versus tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency versus recirculation, or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8+ T cell activation leads to rapid transcriptional reprograming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (TRM). Klf2-deficient memory CD8+ T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest KLF2 diverts CD8+ T cells from the TRM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of TRM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate KLFs occupy a central nexus in coordinating activated CD8+ T cell differentiation and trafficking.

2026-03-10 | GSE324376 | GEO

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Project description:Tissue resident memory T (TRM) cells are non-recirculating lymphocytes that provide localized immunity against intracellular pathogens and cancer. Upon antigen reencounter, TRM cells can differentiate into effector cells and give rise to another generation of memory cells. While considerable heterogeneity of TRM cells has been described, it is unclear how distinct populations contribute to their maintenance or recall capacity. Here we show that TRM cells that express the transcriptional regulators HOBIT, TCF1 and ID3 exhibited precursor-like properties, contributing to the maintenance of the TRM cell pool over time and the reformation of CD103+ TRM cells after recall. TGF-beta (TGF-b) and retinoic acid signalling were required for inducing and maintaining TCF1 and ID3 expression and restrained secondary effector differentiation during reinfection. Finally, we show that TRM cells could differentiate into tissue confined and recirculating CX3CR1+ effector cells thereby contributing to protective immunity during recall. Thus, distinct precursor-like TRM cells contribute to the maintenance of tissue memory and anamnestic secondary memory responses.

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KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3

Project description:KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3

| PRJNA1434513 | ENA

KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3

Project description:KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3

| PRJNA1430833 | ENA

Development pathway for skin resident memory CD103+CD8+ T cells

Project description:Tissue resident memory T cells (TRM) provide superior protection against infection localised to extra-lymphoid compartments in the body. Here we show that CD103+CD8+ TRM cells develop in skin from killer cell lectin-like receptor (KLR)G1-negative precursors that selectively infiltrate the epithelial layer. In the skin, a combination of chemokine-guided epithelial entry, local interleukin (IL)-15 and transforming growth factor (TGF)-Î² signalling is required for formation and survival of these long-lived memory cells. Importantly, TRM differentiation results in the gradual acquisition of a unique transcriptional profile that differs from that expressed by memory cells in the circulation and other types of skin-resident intra-epithelial T cells, such as the dendritic epidermal T cells (DETC). We provide a comprehensive molecular and developmental framework for the local differentiation of a distinct type of peripheral memory T cell that contributes to an important first-line of immune defence in barrier tissues such as skin and mucosa. 24 samples were analyzed: 3 replicates of memory gB-T CD8+. CD103+ T cells isolated from the skin of C57/BL6 mice on day 30 p.i. with HSV KOS. 3 replicates of memory P14 CD8+ T cells isolated from gut of mice on day 60 p.i. with LCMV Armstrong. 3 replicates of memory gB-T CD8+ T cells from the lung of mice on day 30 p.i. with influenza WSN. 3 replicates of memory CD62L high CD8+ T cells from the spleen of mice on day 30 p.i. with HSV KOS. 3 replicates of memory CD62L low CD8+ T cells from the spleen of mice of day 30 p.i. with HSV KOS. 3 replicates of Î³Î´-DETC isolated from the skin of C57/BL6 mice on day 30 p.i. with HSV KOS. 3 replicates of Î±Î²-DETC from naive TCRÎ´-/- mice; and 3 replicates of naive gB-T CD8+ T cells from the spleen of naive gB-T transgenic mice.

2013-10-01 | E-GEOD-47045 | biostudies-arrayexpress

Peripheral and systemic antigens elicit an expandable pool of resident memory CD8+ T cells in the bone marrow

Project description:Bone marrow (BM) has been put forward as a major reservoir for memory CD8+ T cells. In order to fulfill that function, BM should "store" memory CD8+ T cells, which in biological terms would require these "stored" memory cells to be in disequilibrium with the circulatory pool. This issue is a matter of ongoing debate. Here, we unequivocally demonstrate that murine and human BM harbors a population of tissue-resident memory CD8+ T (TRM ) cells. These cells develop against various pathogens, independently of BM infection or local antigen recognition. BM CD8+ TRM cells share a transcriptional program with resident lymphoid cells in other tissues; they are poly-functional cytokine producers and dependent on IL-15, Blimp-1 and Hobit. CD8+ TRM cells reside in the BM parenchyma, but are in close contact with the circulation. Moreover, this pool of resident T cells is not size-restricted and expands upon peripheral antigenic re-challenge. This works extends the role of the BM in the maintenance of CD8+ T cell memory to include the preservation of an expandable reservoir of functional, non-recirculating memory CD8+ T cells, which develop in response to a large variety of peripheral antigens. This article is protected by copyright. All rights reserved.

2019-03-21 | GSE96839 | GEO

Enhancer-driven gene regulatory networks reveal transcription factors governing T cell adaptation and differentiation in the tumor microenvironment.

Project description:Tumor infiltrating lymphocytes (TIL) with a CD8+ T cell tissue-resident memory (Trm) phenotype are associated with improved patient outcomes in solid malignancies. To define programs governing the formation of Trm-like TIL, we performed paired single-cell RNA sequencing and single-cell ATAC sequencing of T cell receptor (TCR)-matched CD8+ T cells in models of infection and cancer. Enhancer-driven regulons assembled from multiomic profiling data revealed epigenetic and transcriptional programs regulating the formation of Trm-like TIL in relation to canonical exhausted and memory T cell states. The transcriptional regulator KLF2 repressed the formation of CD69+CD103+ Trm-like TIL and limited anti-tumor activity. Conversely, sustained expression of the transcription factor BATF enhanced formation of CD69+CD103+ TIL, contingent upon downregulation of KLF2. Transforming growth factor β (TGF-β) signaling and CD103 expression were necessary for Trm-like TIL formation, but BATF overexpression was sufficient to drive formation of CD69+CD103+ TIL in TGFBR2-silenced cells. These findings reveal mechanisms of Trm-like TIL differentiation and provide a framework for considering tissue residency in the context of CD8+ T cell heterogeneity in the tumor microenvironment.

2025-05-26 | GSE267584 | GEO

Enhancer-driven gene regulatory networks reveal transcription factors governing T cell adaptation and differentiation in the tumor microenvironment

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Depleting CD103+ resident memory T cells in vivo reveals immunostimulatory functions in oral mucosa

Project description:The oral mucosa is a frontline for microbial exposure and juxtaposes several unique tissues and mechanical structures. Based on parabiotic surgery of mice receiving systemic viral infections or co-housing with microbially diverse pet shop mice, we report that the oral mucosa harbors CD8+ CD103+ resident memory T cells (TRM), which locally survey tissues without recirculating. Oral antigen reencounter during the effector phase of immune responses potentiated TRM establishment within tongue, gums, palate, and cheek. Upon reactivation, oral TRM triggered changes in somatosensory and innate immune gene expression. We developed in vivo methods for depleting CD103+ TRM while sparing CD103neg TRM and recirculating cells. This revealed that CD103+ TRM were responsible for inducing local gene expression changes. Oral TRM putatively protected against local viral infection. This study provides methods for generating, assessing, and in vivo depleting oral TRM, documents their distribution throughout the oral mucosa, and provides evidence that TRM confer protection and trigger responses in oral physiology and innate immunity.

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