STAT4 increases the phenotypic and functional heterogeneity of intestinal tissue-resident memory T cells

Fung, Helen Y.; Espinal, Angie M.; Teryek, Matthew; Lemenze, Alexander; Bergsbaken, Tessa

doi:10.1016/j.mucimm.2023.03.002

Cited by 3 publications

(2 citation statements)

References 61 publications

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“…Similar this report, we were unable to detect IFNg protein expression in freshly-isolated gd IELs following anti-CD3 treatment by intracellular staining or using IFNg-YFP reporter mice. Based on the attenuation of responsiveness to TCR stimulation within the natural IEL compartment, we posit that virus-specific, induced CD8ab IELs or lamina propria T cells may function as the primary responders to TCR agonist (71,72) and contribute to the production of type I IFN that can subsequently promote an innate, antiviral program in gd IELs as part of a bystander response (73).…”

Section: Discussionmentioning

confidence: 99%

Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes

Fischer,

Jia,

Edelblum

2024

Preprint

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Intraepithelial lymphocytes (IEL) expressing the γδ T cell receptor (TCR) survey the intestinal epithelium to limit the invasion of microbial pathogens. The production of type I interferon (IFN) is a central component of an antiviral immune response, yet how these pro-inflammatory cytokines contribute to γδ IEL effector function remains unclear. Based on the unique activation status of IELs, and their ability to bridge innate and adaptive immunity, we investigated the extent to which type I IFN signaling modulates γδ IEL function. Using an ex vivo culture model, we find that type I IFN alone is unable to drive IFNγ ; production, yet low level TCR activation synergizes with type I IFN to induce IFNγ production in murine γδ IELs. Further investigation into the underlying molecular mechanisms of co-stimulation revealed that TCRγδ-mediated activation of NFAT and JNK is required for type I IFN to promote IFNγ expression in a STAT4-dependent manner. Whereas type I IFN rapidly upregulates antiviral gene expression independent of a basal TCRγδ signal, neither tonic TCR triggering nor the presence of a TCR agonist was sufficient to elicit type I IFN-induced IFNγ production in vivo. However, bypassing proximal TCR signaling events synergized with IFNAR/STAT4 activation to induce γδ IEL IFNγ production. These findings indicate that γδ IELs contribute to host defense in response to type I IFN by mounting a rapid antimicrobial response independent of TCRγδ signaling, and under permissive conditions, produce IFNγ in a TCR-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes

Fischer,

Jia,

Edelblum

2024

Preprint

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“…Afterwards, STAT4 promotes MYD88, IFN‐γ, Tumor necrosis factor (TNF), IL18R1, Furin, and IL18RAP transcription 9 . STAT4 is also a key regulator of memory T‐cell differentiation, and the release of cytokines in natural killer (NK) cell, especially INF‐γ 10,11 . STAT4‐induced transcription factor T‐bet facilitates the expression of IFN‐γ, granzyme B, and perforin, resulting in enhanced NK cell cytotoxicity 12 …”

Section: Introductionmentioning

confidence: 99%

STAT4 facilitates PD‐L1 level via IL‐12R/JAK2/STAT3 axis and predicts immunotherapy response in breast cancer

Zhou,

Wan,

Wang

et al. 2023

MedComm

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Signal transducer and activator of transcription 4 (STAT4) is a critical transcription factor for T helper cell differentiation and tumor cells. Although its prognostic role and gene function have been reported in several carcinomas, the role of STAT4 in vitro and in vivo in breast cancer remains poorly understood. The effect of STAT4 in immunotherapy is also unclear. Therefore, we integrated bulk transcriptomics, experiments, and single‐cell transcriptomics to systematically analyze its function in prognosis and signaling pathway. Several clinical breast cancer cohorts confirmed STAT4 as a T‐cell relevant prognostic biomarker. Overexpressed STAT4 increased programmed cell death ligand 1 (PD‐L1) and major histocompatibility complex class II levels in breast cancer cells. In molecular mechanism, transcriptional synergy between STAT4 and STAT3 transactivated interleukin (IL)‐12R and involved a positive feedback loop: STAT4/IL‐12R/JAK2–STAT3–STAT4, which contributed to the upregulation of PD‐L1 expression. The above signaling axis was defined as the STAT4‐related pathway and its score was used to predict T‐cell expansion and anti‐PD1 treatment response. These findings highlight a novel molecular mechanism indirectly regulating PD‐L1 through the STAT4‐related pathway: IL‐12R/JAK2–STAT3–STAT4/PD‐L1, and it has potential application in predicting anti‐PD‐1 immunotherapy response, which may pave the way for stratified immunotherapy in breast cancer.

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CD8+ Tissue-Resident Memory T Cells: Versatile Guardians of the Tissue

Marchesini Tovar,

Gallen,

Bergsbaken

2024

The Journal of Immunology

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Tissue-resident memory T (Trm) cells are a subset of T cells maintained throughout life within nonlymphoid tissues without significant contribution from circulating memory T cells. CD8+ Trm cells contribute to both tissue surveillance and direct elimination of pathogens through a variety of mechanisms. Reactivation of these Trm cells during infection drives systematic changes within the tissue, including altering the state of the epithelium, activating local immune cells, and contributing to the permissiveness of the tissue for circulating immune cell entry. Trm cells can be further classified by their functional outputs, which can be either subset- or tissue-specific, and include proliferation, tissue egress, and modulation of tissue physiology. These functional outputs of Trm cells are linked to the heterogeneity and plasticity of this population, and uncovering the unique responses of different Trm cell subsets and their role in immunity will allow us to modulate Trm cell responses for optimal control of disease.

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STAT4 increases the phenotypic and functional heterogeneity of intestinal tissue-resident memory T cells

Cited by 3 publications

References 61 publications

Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes

Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes

STAT4 facilitates PD‐L1 level via IL‐12R/JAK2/STAT3 axis and predicts immunotherapy response in breast cancer

CD8+ Tissue-Resident Memory T Cells: Versatile Guardians of the Tissue

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