Linking Innate and Adaptive Immunity: Human Vγ9Vδ2 T Cells Enhance CD40 Expression and HMGB-1 Secretion

γδ T cells play an important role in regulating the immune response to stress stimuli; however, the mean by which these innate lymphocytes fulfill this function remains poorly defined. The main subset of human peripheral blood γδ T cells responds to nonpeptidic antigens, such as isopentylpyrophosphate (IPP), a metabolite in the mevalonate pathway for both eukaryote and prokaryote cells. IPP-primed γδ T cells significantly augment the inflammatory response mediated by monocytes and αβ T cells to TSST-1, the staphylococcal superantigen that is the major causative agent of toxic shock syndrome. Here we show that the small pool of activated peripheral γδ T cells induces an early upregulation of CD40 on monocytes and the local release of High Mobility Group Box-1 (HMGB-1), the molecule designated as the late mediator of systemic inflammation. This finding provides a new basis for how γδ T cells may serve as influential modulators of both endogenous and exogenous stress stimuli

Staphylococcal Toxic Shock Syndrome Toxin-1 Induces the Translocation and Secretion of High Mobility Group-1 Protein from Both Activated T Cells and Monocytes

High mobility group box-1 (HMGB-1) is a DNA-binding protein secreted by activated monocytes and has been identified as a key late mediator of endotoxic shock. We investigated the regulation of HMGB-1 in human peripheral blood mononuclear cells (PBMCs) following stimulation with the staphylococcal superantigen, toxic shock syndrome toxin-1 (TSST-1), and found that TSST-1, like LPS, induced the secretion of HMGB-1 from human PBMC. However, unlike monocyte-driven sepsis caused by endotoxin, translocation and secretion of HMGB-1 mediated by TSST-1 was dependent on the presence of both activated T cells and monocytes. Furthermore, we show that nuclear HMGB-1 is released from TSST-1 stimulated T cells. This finding presents a basis for investigating the potential of targeting HMGB-1 for the treatment of toxic shock syndrome, and provides further insight on the role of HMGB-1 in the cross-talk between activated monocytes and T cells

Innate regulation of TSST-1 induced immune response by peripheral blood γδ T cells

Toxic shock syndrome toxin-1 (TSST-1) is the staphylococcal superantigen (sAg) identified as being the primary causative agent of menstrual toxic shock syndrome (TSS), and it is among the main sAg’s responsible for non-menstrual TSS. Superantigens are the most potent T cell mitogens known. They induce the massive secretion of inflammatory cytokines by bypassing the processing and presentation requirement of conventional peptide antigens and by binding as intact proteins directly to the MHC class II on antigen presenting cells and to specific Vβ-chains of the αβ T cell receptor. This interaction results in an inflammatory cascade that has the potential to lead to hypotension, shock, and death. TSST-1 is expressed by at least 20% of S. aureus clinical isolates; however, not everyone exposed to this sAg succumbs to TSS. Apart from protective antibodies, the factors in the immediate microenvironment which dictate the course of the immune response leading to a deleterious inflammatory reaction are largely unknown. γδ T cells are a unique subset of innate T lymphocytes that are credited with linking the innate and adaptive immune system as they serve as the first line of defense [i.e. defence] against both infectious and non-infectious stress. The objective of this study was to determine if and how human peripheral blood γδ T cells may influence the course of TSST-1 induced inflammation. High mobility group box-1 protein (HMGB-1) was investigated as an indicator of the downstream consequence of γδ T cell activity in TSST-1 pathogenesis. HMGB-1 is a nuclear protein that was previously found to be secreted by LPS-stimulated macrophages, and was determined to be the late mediator of endotoxin shock since neutralizing its effects as late as 24 hours following sepsis was sufficient to rescue mice from lethality. This study established that γδ T cells potently exacerbate the early inflammatory response to TSST-1 and enhance the subsequent secretion of HMGB-1. γδ T cells mediate this effect by inducing early monocyte maturation and upregulating the expression of CD40 which plays a pivotal role in TSST-1 pathogenesis. The results of this study lend support to the notion that γδ T cells play an important role in linking the innate and adaptive immune responses to TSST-1.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat

Premature Spinal Bone Loss in Women Living with HIV is Associated with Shorter Leukocyte Telomere Length

With advances in combination antiretroviral therapy (cART), people living with HIV are now surviving to experience aging. Evidence suggests that individuals living with HIV are at greater risk for low bone mineral density (BMD), osteoporosis, and fractures. Better understanding of the pathophysiology of bone health in women living with HIV (WLWH) is important for treatment strategies. The goal of this study was to explore new biological factors linked to low BMD in WLWH. Standardized BMD measures of WLWH were compared to reference values from an unselected population of women from the same geographical region of the same age range. Linear regression analysis was used to assess relationships among health-related characteristics, cellular aging (measured by leukocyte telomere length; LTL), cART, and BMD of WLWH. WLWH (n = 73; mean age 43 ± 9 years) had lower BMD Z-scores at the lumbar spine (LS) (mean difference = −0.39, p < 0.001) and total hip (TH) (−0.29, p = 0.012) relative to controls (n = 290). WLWH between 50 and 60 years (n = 17) had lower Z-scores at the LS (p = 0.008) and TH (p = 0.027) compared to controls (n = 167). Among WLWH, LS BMD was significantly associated with LTL (R2 = 0.09, p = 0.009) and BMI (R2 = 0.06, p = 0.042). Spinal BMD was adversely affected in WLWH. Reduction of LTL was strongly associated with lower BMD and may relate to its pathophysiology and premature aging in WLWH

Immune Stimulation Using a Gut Microbe-Based Immunotherapy Reduces Disease Pathology and Improves Barrier Function in Ulcerative Colitis

Background: Current ulcerative colitis (UC) treatments are focused on symptom management primarily via immune suppression. Despite the current arsenal of immunosuppressant treatments, the majority of patients with UC still experience disease progression. Importantly, aggressive long-term inhibition of immune function comes with consequent risk, such as serious infections and malignancy. There is thus a recognized need for new, safe and effective treatment strategies for people living with UC that work upstream of managing the symptoms of the disease. The objective of this study was to evaluate a microbial-based treatment, QBECO, that functions to productively activate rather than suppress mucosal immune function as a novel approach to treat UC.Methods: Two established models of experimental colitis, namely chemically-induced DSS colitis and the spontaneous colitis that develops in Muc2 deficient mice, were used to assess whether QBECO treatment could ameliorate gastrointestinal disease. A small exploratory 16-week QBECO open-label trial was subsequently conducted to test the safety and tolerability of this approach and also to determine whether similar improvements in clinical disease and histopathology could be demonstrated in patients with moderate-to-severe UC.Results: QBECO treatment successfully reduced inflammation and promoted mucosal and histological healing in both experimental models and in UC patients. The preclinical models of colitis showed that QBECO ameliorated mucosal pathology, in part by reducing inflammatory cell infiltration, primarily that induced by neutrophils and inflammatory T cells. The most rapid and noticeable change observed in QBECO treated UC patients was a marked reduction in rectal bleeding.Conclusion: Collectively, this work demonstrates for the first time that strategically activating immune function rather than suppressing it, not only does not worsen colitis induced-damage, but may lead to an objective reduction in UC disease pathology