Lung-resident memory CD8 T cells (TRM) induced by influenza A virus (IAV) that are pivotal for providing subtype-transcending protection against IAV infection (heterosubtypic immunity) not maintained long term, causing gradual loss of protection. The short-lived nature lung TRM contrasts sharply with long-term maintenance localized infections in the skin and other tissues. We show decline is determined an imbalance between apoptosis recruitment conversion to circulating cells. effector (TEM)...

The K/BXN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ cells from the KRN strain that are activated glucose-6-phosphate isomerase (GPI) peptides presented H-2g7 allele NOD strain. It autoimmune seropositive because production anti-GPI IgG necessary and sufficient for joint pathology. high levels requires on expansion follicular helper (Tfh) cells. metabolic requirements this have never been characterized. Based therapeutic effects combination metformin...

Abstract Follicular helper T (T FH ) cells are expanded in systemic lupus erythematosus, where they required to produce high affinity autoantibodies. Eliminating would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results a drastic reduction frequency number lupus-prone mice. However, this inhibition has little effect on T-cell-dependent following immunization with an exogenous antigen or...

Abstract There is a finely tuned interplay between immune and neuroendocrine systems. Metabolic disturbances like obesity will have serious consequences on immunity both at the cellular cytokine expression levels. Our in vivo results confirm deficiency of ob/ob mice, leptin deficient massively obese, characterized by reduced Ag-specific T cell proliferation after keyhole limpet hemocyanin immunization. In this report, we show that dendritic cells (DCs), major APCs involved lymphocyte...

Cognate interactions between T follicular helper (Tfh) cells and B are essential for promoting protective Ab responses. Whereas costimulatory receptors such as ICOS accepted being important the induction of Tfh cell fate decision, other molecules may play key roles in amplifying or maintaining phenotype. In this study, with vaccinia virus infection mice, we show that OX40 was expressed on accumulated at T/B borders white pulp spleen OX40-dependent signals directly shaped magnitude quality...

A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs lupus-susceptible mice, and how metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that is differentially catabolized lupus mice compared to controls microbiota played a role this skewing. There was no evidence for differential expression of catabolic enzymes further supporting major contribution However, isolated cells processed...

In establishing a respiratory infection, vaccinia virus (VACV) initially replicates in airway epithelial cells before spreading to secondary sites of mainly the draining lymph nodes, spleen, gastrointestinal tract, and reproductive organs. We recently reported that interferon gamma (IFN-γ) produced by CD8 T ultimately controls this disseminated but relative contribution IFN-γ early infection is unknown. Investigating role innate immune cells, we found frequency natural killer (NK) lung...

Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these the endolysosome is required for signaling response to DNA single-stranded RNA, respectively. Targeting this may represent a novel strategy inhibit TLR-mediated Human alpha 1 antitrypsin (hAAT) protease inhibitor with anti-inflammatory immunoregulatory properties. However, effect hAAT on endosomal TLRs remains elusive. In...

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to xanthosine monophosphate, rate-limiting step in de novo guanosine (GMP) synthesis. In cultured cells, IMPDH polymerizes into micron-scale filamentous structures when GMP synthesis is inhibited by depletion purine precursors or various drugs, including mycophenolic acid, ribavirin, and methotrexate. filaments also spontaneously form undifferentiated mouse embryonic stem cells induced pluripotent hinting they might...

Systemic lupus erythematosus is an autoimmune disease characterized by overproduction of autoantibodies resulting from dysregulation in multiple immune cell types. D-mannose a C

CD8 T cells are a key component of immunity to many viral infections. They achieve this through using an array effector mechanisms, but precisely which component/s required for protection against respiratory orthopox virus infection remains unclear. Using model vaccinia in mice, we could specifically determine the relative contribution perforin, TRAIL, and IFN-γ-mediated pathways induced morbidity mortality. Unexpectedly, observed that death was mediated by IFN-γ without any involvement...

Abstract Phenotypically diverse memory CD 8 + T cells are present in the lungs that either re‐circulate or reside within tissue. Understanding key cellular interactions regulate generation and then persistence of these different subsets is great interest. Recently, DNGR ‐1 dendritic cell ( DC ) mediated priming was reported to control lung‐resident but not circulating following respiratory viral infection. Here, we report an important role for Ly6C inflammatory monocytes IM s) contributing...

During respiratory infection with vaccinia virus (VacV), a member of Poxviridae family, CD8 + T cells play important role in resolving the primary infection. Effector clear by accumulating infected lungs large numbers and secreting molecules such as IFN-γ that kill virally cells. However, precise cell types regulate generation effector are not well defined. Dendritic (DCs) heterogeneous population immune recognized key initiators regulators T-cell-mediated immunity. In this study, we reveal...

Abstract The transition of effector T cells or memory precursors into distinct long-lived cell subsets is not well understood. Although many molecules made by APCs can contribute to clonal expansion and differentiation, it clear if contraction development passive active. Using respiratory virus infection, we found that CD8 cannot express the TNF family molecule lymphotoxin-like, exhibits inducible expression, competes with HSV glycoprotein D for herpes entry mediator, a receptor expressed...

Gut dysbiosis has been associated with lupus pathogenesis, and fecal microbiota transfers (FMT) from lupus-prone mice shown to induce autoimmune activation into healthy mice. The immune cells of patients exhibit an increased glucose metabolism treatments 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, are therapeutic in Here, we showed two models different etiologies that 2DG altered the composition microbiome metabolites. In both models, FMT 2DG-treated protected same strain development...

How tissue-specific anatomical distribution and phenotypic specialization are linked to protective efficacy of memory T cells against reinfection is unclear. Here, we show that lung environmental cues program recently recruited central-like with migratory potentials for their functions during lethal respiratory virus infection. After entering the lung, some retain original CD27hiCXCR3hi phenotype, enabling them localize near infected bronchiolar epithelium airway lumen function as first line...

Abstract The activation of lymphocytes in patients with lupus and mouse models the disease is coupled an increased cellular metabolism which glucose plays a major role. pharmacological inhibition glycolysis 2-deoxy-d-glucose (2DG) reversed expansion follicular helper CD4+ T cells germinal center B lupus-prone mice, as well production autoantibodies. response foreign Ags was however not affected by 2DG these suggesting that cell autoantigens uniquely sensitive to glycolysis. In this study, we...

Abstract Mucosal immunity to reinfection with a highly virulent virus requires the accumulation and persistence of memory CD8 T cells at site primary infection. These may derive from precursor effector (MPECs), which are distinct short-lived that provide acute protection but often destined die. Using respiratory infection, we show herpes entry mediator (HVEM; TNFRSF14), member TNF receptor superfamily, provides key signals for MPEC persistence. HVEM-deficient expanded normally were skewed...

CD8+ T cells play an important role in host resistance to many viral infections, but the underlying transcriptional mechanisms governing their differentiation and functionality remain poorly defined. By using a highly virulent systemic respiratory poxvirus infection mice, we show that transcription factor Bcl11b provides dual trigger sustains clonal expansion of virus-specific effector cells, while simultaneously suppressing expression surface markers associated with short-lived cell (SLEC)...

Patients with systemic lupus erythematosus (SLE) present a high incidence of atherosclerosis, which contributes significantly to morbidity and mortality in this autoimmune disease. An impaired balance between regulatory (Treg) follicular helper (Tfh) CD4+ T cells is shared by both diseases. However, whether there are common mechanisms cell dysregulation SLE atherosclerosis remains unclear. Pre-B leukemia transcription factor 1 isoform d (Pbx1d) susceptibility gene that regulates Tfh...

We report a novel model of lupus-associated cardiovascular pathology accelerated by the TLR7 agonist R848 in lupus-prone B6. Sle1.Sle2.Sle3 (TC) mice. R848-treated TC mice but not non-autoimmune C57BL/6 (B6) controls developed microvascular inflammation and myocytolysis with intracellular vacuolization. This histopathology was similar to antibody-mediated rejection after heart transplant, although it did involve complement. The or B6 recipients serum splenocytes from reactive cardiomyocyte...

Abstract The high-affinity IgE receptor FcεRI and, in some models, the low-affinity IgG FcγRIII/CD16 play an essential role allergic diseases. In human skin, they are present on APCs and effector cells recruited into inflamed dermis. FcRγ is a subunit shared, among other FcRs, by CD16 to their assembly signal transduction. Using experimental model reproducing features of atopic dermatitis specific FcR-deficient mice, we have herein delineated respective contribution pathology. We demonstrate...