TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis

Tatsuno, Kazuki; Fujiyama, Toshiharu; Yamaguchi, Hayato; Waki, Michihiko; Tokura, Y.

doi:10.1038/jid.2015.318

Cited by 81 publications

(84 citation statements)

References 23 publications

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“…4a,b). Since direct interactions between T cells and TSLP have recently been demonstrated 53 , we investigated the role of TSLP on T cell migration. Pre-incubation of T cells with a TSLP receptor antibody inhibited dermal infiltration, while direct application of recombinant human TSLP on the dermis equivalents or T cells cultured in transwells resulted in CD4 + T cell migration (Fig.…”

Section: Discussionmentioning

confidence: 99%

TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents

Wallmeyer

Dietert

Sochorová

et al. 2017

Sci Rep

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Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4+ T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD.

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Section: Discussionmentioning

confidence: 99%

TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents

Wallmeyer

Dietert

Sochorová

et al. 2017

Sci Rep

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“…Although a low level of anti-SmCL3 antibody was detected following a challenge infection of vaccinated mice these were far lower than those observed for SmCB1, suggesting a more prominent infection-associated anamnestic response for the latter peptidase which is supported by it well-known immunogenicity in experimental and natural infection [27]. However, both peptidases stimulated detectable levels of TSLP from EC cells in vitro that suggests a role for this master cytokine of type 2 immune responses [28, 29] in initiating protective responses. Our previous studies have shown that delivery of TSLP to mice induced type-2 related protective immune responses against S .…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have shown that delivery of TSLP to mice induced type-2 related protective immune responses against S . mansoni challenge infection [11], which could have involved the recruitment and activation of eosinophils, basophils, and mast cells [29–36]. …”

Section: Discussionmentioning

confidence: 99%

Protective immune responses against Schistosoma mansoni infection by immunization with functionally active gut-derived cysteine peptidases alone and in combination with glyceraldehyde 3-phosphate dehydrogenase

et al. 2017

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BackgroundSchistosomiasis, a severe disease caused by parasites of the genus Schistosoma, is prevalent in 74 countries, affecting more than 250 million people, particularly children. We have previously shown that the Schistosoma mansoni gut-derived cysteine peptidase, cathepsin B1 (SmCB1), administered without adjuvant, elicits protection (>60%) against challenge infection of S. mansoni or S. haematobium in outbred, CD-1 mice. Here we compare the immunogenicity and protective potential of another gut-derived cysteine peptidase, S. mansoni cathepsin L3 (SmCL3), alone, and in combination with SmCB1. We also examined whether protective responses could be boosted by including a third non-peptidase schistosome secreted molecule, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), with the two peptidases.Methodology/Principal findingsWhile adjuvant-free SmCB1 and SmCL3 induced type 2 polarized responses in CD-1 outbred mice those elicited by SmCL3 were far weaker than those induced by SmCB1. Nevertheless, both cysteine peptidases evoked highly significant (P < 0.005) reduction in challenge worm burden (54–65%) as well as worm egg counts and viability. A combination of SmCL3 and SmCB1 did not induce significantly stronger immune responses or higher protection than that achieved using each peptidase alone. However, when the two peptidases were combined with SG3PDH the levels of protection against challenge S. mansoni infection reached 70–76% and were accompanied by highly significant (P < 0.005) decreases in worm egg counts and viability. Similarly, high levels of protection were achieved in hamsters immunized with the cysteine peptidase/SG3PDH-based vaccine.Conclusions/SignificanceGut-derived cysteine peptidases are highly protective against schistosome challenge infection when administered subcutaneously without adjuvant to outbred CD-1 mice and hamsters, and can also act to enhance the efficacy of other schistosome antigens, such as SG3PDH. This cysteine peptidase-based vaccine should now be advanced to experiments in non-human primates and, if shown promise, progressed to Phase 1 safety trials in humans.

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“…TSLP receptor is preferentially expressed on dividing human T H 2 cells isolated from allergic subjects 53 and on skin-homing T H 2 cells (CLA + CCR4 + CXCR3 − ) in patients with AD. 54 Moreover, skin-homing T cells increase their expression of TSLP receptor in response to IL-4 and enhance their secretion of IL-4 in response to TSLP, forming a positive feed-forward loop. T H 2 cells also positively feedback on epithelial cells in the allergic host to enhance their production of TSLP.…”

Section: Tslpmentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis

Cited by 81 publications

References 23 publications

TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents

TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents

Protective immune responses against Schistosoma mansoni infection by immunization with functionally active gut-derived cysteine peptidases alone and in combination with glyceraldehyde 3-phosphate dehydrogenase

Pathogenic CD4 + T cells in patients with asthma

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