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Cation homeostasis, in relation to various immunesuppressive diseases, is a novel field of investigation. Recently, patients with a loss-of-function mutation in magnesium transporter 1 (MAGT1) were reported to present a dysregulated Mg2+ homeostasis in T lymphocytes. Using Magt1-knockout mice (Magt1-ly), we show that Mg2+ homeostasis was impaired in Magt1-ly B cells and Ca2+ influx was increased after BCR stimulation, whereas T and NK cell function was unaffected. Consequently, mutant B cells displayed an increased phosphorylation of BCR-related proteins differentially affecting protein kinase C activation. These in vitro findings translated into increased frequencies of CD19+ B cells and marginal zone B cells and decreased frequencies of plasma cells among CD45+ splenocytes in vivo. Altogether, our study demonstrates for the first time, to our knowledge, that abolished MAGT1 function causes imbalanced cation homeostasis and developmental responses in B cells. Therefore, this study might contribute to a further understanding of B cell-related pathologies. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4+ effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4+ CD45RA+CD25++) and higher frequencies of IFN-g+ and/or IL-4+ cells were detected among CD4+ T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17+ cells among intrahepatic CD4+ T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17+ cells among intrahepatic CD4+ T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood. [ABSTRACT FROM AUTHOR]

Because of the growing numbers of immunocompromised patients, the incidence of life-threatening fungal infections caused by Candida albicans and Aspergillus fumigatus is increasing. We have recently identified enolase 1 (Eno1) from A. fumigatus as an immune evasion protein. Eno1 is a fungal moonlighting protein that mediates adhesion and invasion of human cells and also immune evasion through complement inactivation. We now show that soluble Eno1 has immunostimulatory activity. We observed that Eno1 from both C. albicans and A. fumigatus directly binds to the surface of lymphocytes, preferentially human and mouse B cells. Functionally, Eno1 upregulated CD86 expression on B cells and induced proliferation. Although the receptor for fungal Eno1 on B lymphocytes is still unknown, the comparison of B cells from wild-type and MyD88-deficient mice showed that B cell activation by Eno1 required MyD88 signaling. With respect to infection biology, we noted that mouse B cells stimulated by Eno1 secreted IgM and IgG2b. These Igs bound C. albicans hyphae in vitro, suggesting that Eno1-induced Ab secretion might contribute to protection from invasive fungal disease in vivo. Eno1 also triggered the release of proinflammatory cytokines from monocytes, particularly IL-6, which is a potent activator of B cells. Together, our data shed new light on the role of secreted Eno1 in infections with C. albicans and A. fumigatus. Eno1 secretion by these pathogenic microbes appears to be a double-edged sword by supporting fungal pathogenicity while triggering (antifungal) immunity., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Because of its size, anatomical similarities, and now also accessibility to genetic manipulations, pigs are used as animal models for human diseases and immune system development. However, expression and function of CD28, the most important costimulatory receptor expressed by T cells, so far is poorly understood in this species. Using a newly generated mAb (mAb 3D11) with specificity for pig CD28, we detected CD28 on CD8 + and CD4 + αβ T cells. Among γδ T cells, CD28 expression was restricted to a small CD2 + subpopulation of phenotypically naive cells. Functionally, CD28 ligation with mAb 3D11-costimulated porcine T cells, enhanced proliferation and cytokine secretion in vitro. We used a second, likewise newly generated but superagonistic, anti-CD28 mAb (CD28-SA; mAb 4D12) to test the function of CD28 on porcine T cells in a pilot study in vivo. Injection of the CD28-SA into pigs in vivo showed a very similar dose-response relationship as in humans (i.e., 100 µg/kg body weight [BW]) of CD28-SA induced a cytokine release syndrome that was avoided at a dose of 10 µg/kg BW and below. The data further suggest that low-dose (10 µg/kg BW) CD28-SA infusion was sufficient to increase the proportion of Foxp3 + regulatory T cells among CD4 + T cells in vivo. The pig is thus a suitable animal model for testing novel immunotherapeutics. Moreover, data from our pilot study in pigs further suggest that low-dose CD28-SA infusion might allow for selective expansion of CD4 + regulatory T cells in humans., (Copyright © 2021 by The American Association of Immunologists, Inc.)

CD4 + Foxp3 + regulatory T cells (Tregs) depend on CD28 signaling for their survival and function, a receptor that has been previously shown to activate the acid sphingomyelinase (Asm)/ceramide system. In this article, we show that the basal and CD28-induced Asm activity is higher in Tregs than in conventional CD4 + T cells (Tconvs) of wild-type (wt) mice. In Asm-deficient (Smpd1 -/- ; Asm -/- ) mice, as compared with wt mice, the frequency of Tregs among CD4 + T cells, turnover of the effector molecule CTLA-4, and their suppressive activity in vitro were increased. The biological significance of these findings was confirmed in our Treg-sensitive mouse model of measles virus (MV) CNS infection, in which we observed more infected neurons and less MV-specific CD8 + T cells in brains of Asm -/- mice compared with wt mice. In addition to genetic deficiency, treatment of wt mice with the Asm inhibitor amitriptyline recapitulated the phenotype of Asm-deficient mice because it also increased the frequency of Tregs among CD4 + T cells. Reduced absolute cell numbers of Tconvs after inhibitor treatment in vivo and extensive in vitro experiments revealed that Tregs are more resistant toward Asm inhibitor-induced cell death than Tconvs. Mechanistically, IL-2 was capable of providing crucial survival signals to the Tregs upon inhibitor treatment in vitro, shifting the Treg/Tconv ratio to the Treg side. Thus, our data indicate that Asm-inhibiting drugs should be further evaluated for the therapy of inflammatory and autoimmune disorders., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Store-operated Ca(2+) entry (SOCE) is believed to be of pivotal importance in T cell physiology. To test this hypothesis, we generated mice constitutively lacking the SOCE-regulating Ca(2+) sensor stromal interaction molecule 1 (STIM1). In vitro analyses showed that SOCE and Ag receptor complex-triggered Ca(2+) flux into STIM1-deficient T cells is virtually abolished. In vivo, STIM1-deficient mice developed a lymphoproliferative disease despite normal thymic T cell maturation and normal frequencies of CD4(+)Foxp3(+) regulatory T cells. Unexpectedly, STIM1-deficient bone marrow chimeric mice mounted humoral immune responses after vaccination and STIM1-deficient T cells were capable of inducing acute graft-versus-host disease following adoptive transfer into allogeneic hosts. These results demonstrate that STIM1-dependent SOCE is crucial for homeostatic T cell proliferation, but of much lesser importance for thymic T cell differentiation or T cell effector functions.