Th17 cells, CD4(+) T cells that secrete interleukin-17 (IL-17), are pathogenic in autoimmune diseases and their development and expansion is driven by the cytokines IL-6, TGF-beta, IL-21, IL-1, and IL-23. However, there are also innate sources of IL-17. Here, we show that gammadelta T cells express IL-23R and the transcription factor RORgammat and produce IL-17, IL-21, and IL-22 in response to IL-1beta and IL-23, without T cell receptor engagement. IL-17-producing gammadelta T cells were found at high frequency in the brain of mice with experimental autoimmune encephalomyelitis (EAE). gammadelta T cells activated by IL-1beta and IL-23 promoted IL-17 production by CD4(+) T cells and increased susceptibility to EAE, suggesting that gammadelta T cells act in an amplification loop for IL-17 production by Th17 cells. Our findings demonstrate that gammadelta T cells activated by IL-1beta and IL-23 are an important source of innate IL-17 and IL-21 and provide an alternative mechanism whereby IL-1 and IL-23 may mediate autoimmune inflammation.

SummaryMultiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4 + T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting gd T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, gd, CD8+ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

SummaryBackground There is a dearth of information on the precise pathogenesis of hidradenitis suppurativa (HS), but immune dysregulation is implicated. Objectives To determine the nature of the immune response in HS. Methods Skin biopsies -lesional, perilesional (2 cm away) and uninvolved (10 cm away) -were obtained from patients with HS and healthy controls. The expression of various cytokines was determined by enzyme-linked immunosorbent assay, flow cytometry and real-time polymerase chain reaction. Results The expression of the inflammatory cytokines interleukin (IL)-17, IL-1b and tumour necrosis factor-a was enhanced in lesional skin of patients with HS. In addition, IL17A and IL1B mRNA were enhanced in clinically normal perilesional skin. CD4 + T cells produced IL-17 in HS, while CD11c + CD1a À CD14

Abstract-Notch signaling has been shown recently to regulate vascular cell fate in adult cells. By applying a uniform equibiaxial cyclic strain to vascular smooth muscle cells (SMCs), we investigated the role of strain in modulating Notch-mediated growth of SMCs in vitro. Rat SMCs cultured under conditions of defined equibiaxial cyclic strain (0% to 15% stretch; 60 cycles/min; 0 to 24 hours) exhibited a significant temporal and force-dependent reduction in Notch 3 receptor expression, concomitant with a significant reduction in Epstein Barr virus latency C promoter-binding factor-1/recombination signal-binding protein of the J immunoglobulin gene-dependent Notch target gene promoter activity and mRNA levels when compared with unstrained controls. The decrease in Notch signaling was Gi-proteinand mitogen-activated protein kinase-dependent. In parallel cultures, cyclic strain inhibited SMC proliferation (cell number and proliferating cell nuclear antigen expression) while significantly promoting SMC apoptosis (annexin V binding, caspase-3 activity and bax/bcl-x L ratio). Notch 3 receptor overexpression significantly reversed the straininduced changes in SMC proliferation and apoptosis to levels comparable to unstrained control cells, whereas Notch inhibition further potentiated the changes in SMC apoptosis and proliferation. These findings suggest that cyclic strain inhibits SMC growth while enhancing SMC apoptosis, in part, Key Words: notch Ⅲ cyclic strain Ⅲ apoptosis Ⅲ proliferation Ⅲ vascular Ⅲ G-proteins H emodynamic forces associated with the flow of blood play an important role in the physiological control of vascular tone, remodeling, and associated vascular pathologies. These forces include cyclic circumferential strain, which is caused by a transmural force acting perpendicular to the vessel wall. [1][2][3][4] Mechanotransduction is known to play a central role in the highly coordinated cellular response of the vasculature to changes in hemodynamic stimulation. Transduction of biomechanical stimuli leads to activation of cellular signaling mechanisms that ultimately lead to adaptive, and sometimes maladaptive, changes in cell and tissue fate. 5,6 The ultimate arbiter of vascular cell fate (growth, migration, differentiation, and apoptosis) in response to hemodynamic stimulation is unclear but considered fundamental to the pathogenesis of vascular disease. Strain-induced changes in smooth muscle cell (SMC) growth, defined as the balance between SMC proliferation and apoptosis, participates in the local vascular reaction to hypertension, 3,7 late lumen loss, and restenosis after vascular interventions, as well as plaque vulnerability during athersosclerosis. 1,8 Because changes in vascular cell fate are also apparent during vascular morphogenesis and modeling of the embryonic vasculature, 9,10 the control of these cell fate decisions in adult cells may share similar signaling patterns. Notch receptor-ligand interactions are a highly conserved mechanism, originally described in developmental studies using...