Sensing and alarm function of resident memory CD8+ T cells

Schenkel, Jason M.; Fraser, Kathryn; Vezys, Vaiva; Masopust, David

doi:10.1038/ni.2568

Cited by 531 publications

(602 citation statements)

References 31 publications

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“…Trm cells are a recently described memory T cell subset that are generated at sites of pathogen entry and remain at those sites poised to respond rapidly on re-infection [45]. They have been shown not only to clear infection but also coordinate the early recall response by recognition of antigen and cytokine production in an innate-like manner, altering the inflammatory environment to further recruit other memory T cells [46]. Thus, they are highly specialised to confer early protection, have been shown to provide heterosubtypic immunity against multiple strains of influenza and are strong candidates for the enhancement of vaccine-mediated immunity [47].…”

Section: Experimental Challenge Provides Insights Into Pathogenesismentioning

confidence: 99%

Controlled human infection with RSV: The opportunities of experimental challenge

Habibi

Chiu

2017

Vaccine

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Section: Experimental Challenge Provides Insights Into Pathogenesismentioning

confidence: 99%

Controlled human infection with RSV: The opportunities of experimental challenge

Habibi

Chiu

2017

Vaccine

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“…The improved prognosis is due to the capacity of T RM cells to produce IFN‐γ upon in‐situ antigen recognition [11], resulting in the recruitment of circulating T cells from the blood [12]. Furthermore, the cytotoxic capacity of T RM cells against tumour cells is demonstrated by their production of the cytotoxic mediators, perforin, granzyme A, and granzyme B upon CD103/E‐cadherin ligation and T cell receptor (TCR) activation [8].…”

Section: Introductionmentioning

confidence: 99%

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Hartana

Bergman

Broomé

et al. 2018

Clinical and Experimental Immunology

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SummaryTissue‐resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty‐three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in‐vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin‐expressing TRM cells. Surprisingly, programmed cell death 1 (PD‐1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin‐15 and T cell receptor stimulation, perforin and T‐bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

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“…Cytokines such as IL-15 and TGF-β play important roles in the formation of Trm cells [33], and the molecular signature of Trm cells, including a specific set of transcription factors, chemokines, and inhibitory receptors, has been reported [34]. The mechanisms underlying the development and maintenance of Trm CD8 + T cells, however, remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8⁺ T cells

et al. 2014

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T cells express multiple integrin molecules. The significance of signaling through these molecules on acquisition of T-cell effector functions and memory formation capacity remains largely unknown. Moreover, the impact of stimulation through these signals on the generation of T cells for adoptive immunotherapy has not been elucidated. In this study, using a recombinant fragment of fibronectin, CH-296, we demonstrated that stimulation via very late Ag (VLA)-4 and VLA-5 in human and BALB/c mouse CD8 + T cells, in combination with TCR stimulation, enhances effector multifunctionality and in vivo memory formation. Using TCR-transgenic mouse-derived CD8 + T cells expressing TCR specific for the syngeneic CMS5 fibrosarcoma-derived tumor Ag, we showed that stimulation by CH-296 improved the ability of tumor-specific CD8 + T cells to inhibit CMS5 tumor growth when adoptively transferred into hosts with progressing tumors. Improved antitumor effects were associated with decreased infiltration of Foxp3 + CD4 + Treg cells in tumors. These results suggest that stimulation via VLA-4 and VLA-5 modulates the qualities of effector T cells and could potentially increase the efficacy of adoptive therapy against cancer.Keywords: CD8 + T cells r Integrins r Multifunctionality r Tumor immunology r Very late antigen (VLA) Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Hiroaki Ikeda e-mail: hikeda@clin.medic.mie-u.ac.jp IntroductionT cells express a number of surface molecules that mediate cell-tocell interactions, as well as binding of cells to extracellular matrix proteins [1][2][3]. Several of these adhesion receptors belong to the β1 subfamily of integrin molecules, also known as very late Ag (VLA) molecules, which are characterized by at least nine α-chains C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1748 Hayato Hosoi et al. Eur. J. Immunol. 2014. 44: 1747-1758 that share a noncovalently linked β-chain. Some of these receptors function not only as adhesion molecules but also as transducers of signals in T cells [3][4][5][6]. Several laboratories have shown that binding of human or mouse T cells to fibronectin can induce proliferation via VLA-4 (α4β1) and/or VLA-5 (α5β1) [7][8][9]. Consistent with these reports, we have shown that exposure to CH-296 (RetroNectin), a recombinant human fibronectin fragment that contains the binding domains for VLA-4 and -5, in conjunction with stimulation with anti-CD3 mAbs, promotes T-cell expansion while preserving the CD45RA high CCR7 high phenotype [10]. These results prompted us to investigate whether stimulation via VLA-4 and -5 modulates not only expansion of T cells but also their effector functions and in vivo fates. Cytotoxic T lymphocytes (CTLs) play critical roles in controlling tumor cells [11,12], and the adoptive cell transfer of tumorreactive CTLs is a promising strategy for immunological intervention against cancer [12][13][14]. For clinical applications, T cells of de...

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Sensing and alarm function of resident memory CD8+ T cells

Cited by 531 publications

References 31 publications

Controlled human infection with RSV: The opportunities of experimental challenge

Controlled human infection with RSV: The opportunities of experimental challenge

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8⁺ T cells

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Sensing and alarm function of resident memory CD8+ T cells

Cited by 531 publications

References 31 publications

Controlled human infection with RSV: The opportunities of experimental challenge

Controlled human infection with RSV: The opportunities of experimental challenge

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8+ T cells

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Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8⁺ T cells