mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis.

The accumulation of myofibroblasts within the intimal layer of inflamed blood vessels is a potentially catastrophic complication of vasculitis, which can lead to arterial stenosis and ischaemia. In this study, we have investigated how these luminal myofibroblasts develop during Kawasaki disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that luminal myofibroblasts develop independently of adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs).

Mechanistic Target of Rapamycin Inhibition Prevents Coronary Artery Remodeling in a Murine Model of Kawasaki Disease.

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.

Intimal macrophages develop from circulating monocytes during vasculitis.

Objective: Vasculitis is characterised by inflammation of the blood vessels. While all layers of the vessel can be affected, inflammation within the intimal layer can trigger thrombosis and arterial occlusion and is therefore of particular clinical concern. Given this pathological role, we have examined how intimal inflammation develops by exploring which (and how) macrophages come to populate this normally immune-privileged site during vasculitis.

The Selective Expansion and Targeted Accumulation of Bone Marrow-Derived Macrophages Drive Cardiac Vasculitis.

The adult heart contains macrophages derived from both embryonic and adult bone marrow (BM)-derived precursors. This population diversity prompted us to explore how distinct macrophage subsets localize within the heart, and their relative contributions in cardiac disease. In this study, using the reciprocal expression of Lyve-1 and Ccr2 to distinguish macrophages with distinct origins, we show that, in the steady state, both embryonic (Lyve) and BM-derived (Ccr2) macrophages populate the major vessels of the heart in mice and humans.

TNF and IL-1 Play Essential but Temporally Distinct Roles in Driving Cardiac Inflammation in a Murine Model of Kawasaki Disease.

Kawasaki disease (KD) is a leading cause of pediatric heart disease, characterized by the emergence of life-threatening coronary vasculitis. Identifying which cytokines drive KD has been a major research goal, and both TNF and IL-1 have been identified as potential candidates. Using a murine model of KD induced by the injection of the water-soluble component of , we therefore undertook a mechanistic study to determine how and when these two cytokines mediate cardiac inflammation.

GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease.

Kawasaki disease (KD) is the leading cause of pediatric heart disease in developed countries. KD patients develop cardiac inflammation, characterized by an early infiltrate of neutrophils and monocytes that precipitates coronary arteritis. Although the early inflammatory processes are linked to cardiac pathology, the factors that regulate cardiac inflammation and immune cell recruitment to the heart remain obscure.

T Cell Help Amplifies Innate Signals in CD8(+) DCs for Optimal CD8(+) T Cell Priming.

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.

Distinct epigenetic signatures delineate transcriptional programs during virus-specific CD8(+) T cell differentiation.

The molecular mechanisms that regulate the rapid transcriptional changes that occur during cytotoxic T lymphocyte (CTL) proliferation and differentiation in response to infection are poorly understood. We have utilized ChIP-seq to assess histone H3 methylation dynamics within naive, effector, and memory virus-specific T cells isolated directly ex vivo after influenza A virus infection. Our results show that within naive T cells, codeposition of the permissive H3K4me3 and repressive H3K27me3 modifications is a signature of gene loci associated with gene transcription, replication, and cellular differentiation.

Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection.

Infection induces the expression of inflammatory chemokines that recruit immune cells to the site of inflammation. Whereas tissues such as the intestine and skin express unique chemokines during homeostasis, whether different tissues express distinct chemokine profiles during inflammation remains unclear. With this in mind, we performed a comprehensive screen of the chemokines expressed by two tissues (skin and sensory ganglia) infected with a common viral pathogen (herpes simplex virus type 1).

The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin.

Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) 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.

Vitamin A notches up CD11b hi DC development.

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.

Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation.

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.

Reactive murine lymph nodes uniquely permit parenchymal access for T cells that enter via the afferent lymphatics.

Whereas naïve T cells access the lymph nodes predominantly via the high endothelial venules, their effector counterparts can also enter via the afferent lymphatics. It is unclear if such cells are confined to the lymphatic spaces during their transit through the lymph node or whether they can access the lymphocyte- and dendritic cell-rich parenchyma with its potentially stimulatory environment. We used a flank HSV inoculation model that featured neuronal-mediated movement of virus to distinct areas of skin to study the lymphatic-mediated transit of activated T cells between different skin-draining lymph nodes.

Rapid recruitment and activation of CD8+ T cells after herpes simplex virus type 1 skin infection.

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).

Optimization of TCR transgenic T cells for in vivo tracking of immune responses.

T-cell receptor (TCR) transgenic mice have proven useful for the study of various immune parameters. Despite this, it has been suggested that transferred T cells respond differently to their endogenous counterparts at least in terms of conversion to antigen-experienced populations bearing memory cell markers. Here, we have compared the response of TCR transgenic T cells to endogenous populations within the context of infection with herpes simplex virus.

CTL response compensation for the loss of an immunodominant class I-restricted HSV-1 determinant.

The T-cell response to even complex pathogens is often focused on only a handful of immunodominant determinants. Such narrow responses provoke a selective pressure that can drive the emergence of CTL escape variants, raising the question of whether a broader response, targeting multiple non-dominant peptides may be more beneficial. To examine the ability of the T-cell repertoire to respond to non-dominant determinants, we have investigated how mutating the dominant peptide in HSV affects the magnitude of the CD8+ T-cell response.

Cutting edge: central memory T cells do not show accelerated proliferation or tissue infiltration in response to localized herpes simplex virus-1 infection.

Memory T cells mount an enhanced response to secondary infections. Such an enhancement has been attributed in part to the ability of memory cells to more rapidly respond to cognate stimulation. In this study we have examined the rapidity with which murine CD8(+) memory T cells respond to a localized infection with HSV.

CD4+ T cells can protect APC from CTL-mediated elimination.

Professional APC play a central role in generating antiviral CD8(+) CTL immunity. However, the fate of such APC following interaction with these same CTL remains poorly understood. We have shown previously that prolonged Ag presentation persists in the presence of a strong CTL response following HSV infection.

Cutting edge: prolonged antigen presentation after herpes simplex virus-1 skin infection.

It has been reported that MHC class I-restricted Ag presentation persists for only a short period following infection with certain pathogens, declining in parallel with the emergence of specific CTL activity. We have examined this issue in the case of murine infection with HSV-1. We found that the period of Ag presentation capable of priming naive CD8(+) T cells is comparatively prolonged, persisting for at least 7 days after infection, and continuing despite the appearance of localized CTL activity.