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Objective: Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts, which can lead to coronary artery aneurysms, stenosis, and myocardial ischemia. We undertook this study to investigate whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD. Method: We used a murine model of KD (induced by the injection of the Candida albicans water‐soluble complex [CAWS]) and analyzed patient samples to evaluate potential antifibrotic therapies for KD. Results: We identified the mechanistic target of rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts up‐regulated mTOR kinase signaling in vivo in the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS‐injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries up‐regulate mTOR signaling, confirming that the mTOR pathway is active in human KD. Conclusion: Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high‐risk KD patients. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T cells (TRM cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103+CD8+ TRM cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into TRM cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues. [ABSTRACT FROM AUTHOR]

Vitamin A and its metabolite retinoic acid influence various aspects of immunity. Although the capacity of vitamin A to condition intestinal CD103+ DCs to imprint tissue-specific homing programs onto activated lymphocytes is well documented, it is unclear whether vitamin A also regulates DC populations in other tissues. A study published in this issue of the European Journal of Immunology, Beijer et al. [Eur. J. Immunol. 2013. 43: 1608-1616] now demonstrates that vitamin A exerts profound effects on the subset composition of splenic DCs. By resolving that splenic ESAMhi CD11bhi DCs are preferentially responsive to regulation by vitamin A, these novel insights not only further support the notion that ESAM expression marks two distinct lineages of splenic CD11bhi DCs, but also provide an important extension to our understanding of how vitamin A influences the immune system. [ABSTRACT FROM AUTHOR]

Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (TRM) cells are identified by their expression of the α-chain from the integrin αE(CD103)β7, and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103+CD8+ TRM cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the TRM phenotype. The CD8+ TRM cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral TRM cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection. [ABSTRACT FROM AUTHOR]

After localized infection, naive antigen-specific T cells must localize to those lymph nodes (LNs) draining the site of infection before engaging antigen-bearing dendritic cells. Given that naive precursors are initially distributed randomly throughout the secondary lymphoid compartment, it is unclear how long it takes most antigen-specific precursors to mobilize to draining LNs and become recruited into the primary T cell response. Here, we have examined the kinetics of these events, measuring the period over which naive precursors are recruited into the primary T cell response after cutaneous infection with herpes simplex virus type 1 (HSV-1). We show that despite prolonged MHC class-I-restricted antigen presentation, most naive HSV-specific precursors were recruited from the circulation in the first 4 days after inoculation. Furthermore, this prolonged presentation was also not essential for memory development, as truncating the period of antigen presentation to around 4 days did not affect the level of contraction, or long-term stability of the HSV-specific CD8+ memory T cell pool. Thus, despite initially being dispersed throughout the entire circulation, the recruitment of naive precursors is achieved quite quickly, even when priming is restricted to a small number of draining LNs. [ABSTRACT FROM AUTHOR]

DCs often require stimulation from CD4(+) T cells to propagate CD8(+) T cell responses, but precisely how T cell help optimizes the priming capacity of DCs and why this appears to differ between varying types of CD8(+) T cell immunity remains unclear. We show that CD8(+) T cell priming upon HSV-1 skin infection depended on DCs receiving stimulation from both IFN-α/β and CD4(+) T cells to provide IL-15. This was not an additive effect but resulted from CD4(+) T cells amplifying DC production of IL-15 in response to IFN-α/β. We also observed that increased innate stimulation reversed the helper dependence of CD8(+) T cell priming and that the innate stimulus, rather than the CD4(+) T cells themselves, determined how "help'" was integrated into the priming response by DCs. These findings identify T cell help as a flexible means to amplify varying suboptimal innate signals in DCs., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Vitamin A and its metabolite retinoic acid influence various aspects of immunity. Although the capacity of vitamin A to condition intestinal CD103(+) DCs to imprint tissue-specific homing programs onto activated lymphocytes is well documented, it is unclear whether vitamin A also regulates DC populations in other tissues. A study published in this issue of the European Journal of Immunology, Beijer et al. [Eur. J. Immunol. 2013. 43: 1608-1616] now demonstrates that vitamin A exerts profound effects on the subset composition of splenic DCs. By resolving that splenic ESAM(hi) CD11b(hi) DCs are preferentially responsive to regulation by vitamin A, these novel insights not only further support the notion that ESAM expression marks two distinct lineages of splenic CD11b(hi) DCs, but also provide an important extension to our understanding of how vitamin A influences the immune system., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (T(RM)) cells are identified by their expression of the α-chain from the integrin α(E)(CD103)β(7), and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103(+)CD8(+) T(RM) cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the T(RM) phenotype. The CD8(+) T(RM) cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral T(RM) cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.