Amphiregulin-producing γδ T cells are vital for safeguarding oral barrier immune homeostasis

Krishnan, Siddharth; Prise, Ian; Wemyss, Kelly; Schenck, L. Patrick; Bridgeman, Hayley; McClure, Flora A.; Zangerle-Murray, Tamsin; O’Boyle, Conor; Barbera, Thomas; Mahmood, Faiza; Bowdish, Dawn M. E.; Zaiss, Dietmar M.; Grainger, John; Konkel, Joanne E.

doi:10.1073/pnas.1802320115

Cited by 80 publications

(106 citation statements)

References 37 publications

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“…1 B and Table S1). Among highly enriched genes were also the cytokine CSF1 (M-CSF; Mamedov et al, 2018), the wound-healing associated cytokine amphiregulin (Guo et al, 2018; Krishnan et al, 2018), and the chemokines CCL4 and XCL1 (Table S1). At late gestation, mouse thymocytes (Vγ6 + ) are programmed to make IL17 (Haas et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

The human fetal thymus generates invariant effector γδ T cells

Tieppo

Papadopoulou

Gatti

et al. 2019

Journal of Experimental Medicine

137

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In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming and age-dependent generation of invariant γδ T cells occur in humans is not known. Here we found that, unlike postnatal γδ thymocytes, human fetal γδ thymocytes were functionally programmed (e.g., IFNγ, granzymes) and expressed low levels of terminal deoxynucleotidyl transferase (TdT). This low level of TdT resulted in a low number of N nucleotide insertions in the complementarity-determining region-3 (CDR3) of their TCR repertoire, allowing the usage of short homology repeats within the germline-encoded VDJ segments to generate invariant/public cytomegalovirus-reactive CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY, and TRDV1-TRDD3-CALGELGD). Furthermore, both the generation of invariant TCRs and the intrathymic acquisition of effector functions were due to an intrinsic property of fetal hematopoietic stem and precursor cells (HSPCs) caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in an HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.

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Section: Resultsmentioning

confidence: 99%

The human fetal thymus generates invariant effector γδ T cells

Tieppo

Papadopoulou

Gatti

et al. 2019

Journal of Experimental Medicine

137

View full text Add to dashboard Cite

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“…There is a significant association between periodontitis and plaque psoriasis and an even stronger link to PsA (Egeberg et al, 2017). Experimental models pointed toward a contribution of mechanical stress, i.e., mastication, as well as involvement of dysbiotic oral microbiota to the activation of inflammatory gingival Th17 cells and γδ17 cells (Dutzan et al, 2017(Dutzan et al, , 2018Krishnan et al, 2018;Wilharm et al, 2019). The concept that mechanical signals can trigger innate IL-17 production, while shown in periodontal inflammation, have also been discussed for AS (Reinhardt et al, 2016;Sherlock et al, 2012) and may also be applicable to psoriasis.…”

Section: Current Therapies Targeting Il-17 Cytokinesmentioning

confidence: 99%

Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

Prinz

Sandrock

Mrowietz³

2019

Journal of Experimental Medicine

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The IL-17 cytokine family comprising IL-17A to IL-17F and receptor subunits IL-17RA to IL-17RE represents a genetically ancient intercellular network regulating local tissue homeostasis. Its pivotal role in antifungal defense and its central position in the pathogenesis of inflammatory diseases including psoriasis were discovered only relatively late in the early 2000s. Since the connection of dysregulated IL-17 and psoriasis pathogenesis turned out to be particularly evident, a number of monoclonal antibodies targeting IL-17 pathways have been approved and are used as first line treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis, and further agents are currently in clinical development.

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“…Amphiregulin is an EGF‐like growth factor associated with a number of different physiological processes, such as tissue homeostasis, inflammation and immunity . With regard to tissue homeostasis, a direct role for Amphiregulin has, for instance, recently been demonstrated for the gingiva . The gingiva is a key oral barrier site and Amphiregulin gene‐deficient mice showed at steady‐state a substantially elevated level of oral, periodontal pathology in comparison to wild‐type mice .…”

Section: Non‐immune‐mediated Roles Of Regulatory T‐cells During Woundmentioning

confidence: 99%

“…23,24 With regard to tissue homeostasis, a direct role for Amphiregulin has, for instance, recently been demonstrated for the gingiva. 25 The gingiva is a key oral barrier site and Amphiregulin gene-deficient mice showed at steady-state a substantially elevated level of oral, periodontal pathology in comparison to wild-type mice. 25 Furthermore, during wound healing, a direct role of Amphiregulin has been suggested.…”

Section: Non-immune-mediated Roles Of Regulatory T-cells During Woundmentioning

confidence: 99%

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

2019

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Summary The immune system has a well‐established contribution to tissue homeostasis and wound healing. However, in many cases immune responses themselves can cause severe tissue damage. Thus, the question arose to which extent cells of the immune system directly contribute to the process of wound healing and to which extent the resolution of excessive immune responses may indirectly contribute to wound healing. FoxP3‐expressing CD4 T‐cells, so‐called regulatory T‐cells (Tregs), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that Tregs next to an immune‐regulatory, ‘damage‐limiting’ function may also have an immune‐independent ‘damage‐resolving’ direct role in wound healing. In particular, the release of the epidermal growth factor‐like growth factor Amphiregulin by tissue‐resident Tregs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bio‐active transforming growth factor (TGF)β, a cytokine involved both in immune regulation as well as in the process of wound repair. In light of these findings, we discuss whether, by locally activating TGFβ, Treg‐derived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that Treg‐derived Amphiregulin in an autocrine way may enable an IL‐33‐mediated survival and expansion of tissue‐resident Tregs upon injury. Furthermore, Treg‐derived Amphiregulin may contribute to a constitutive, low‐level release of bio‐active TGFβ within tissues, leading to continuous tissue regeneration and to an immune‐suppressive environment, which may keep inflammation‐prone tissues in an homeostatic state.

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Amphiregulin-producing γδ T cells are vital for safeguarding oral barrier immune homeostasis

Cited by 80 publications

References 37 publications

The human fetal thymus generates invariant effector γδ T cells

The human fetal thymus generates invariant effector γδ T cells

Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

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