ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels ...of ICOS
T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr
-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr
-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.
The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes ...primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138
Blimp1
splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.
Abstract
The inducible T-cell costimulator (ICOS) is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis ...patients were shown to have elevated levels of ICOS+ T cells in the synovial fluid suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS-mediated phosphoinositide 3-kinase (PI3K) signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, ICOS-mediated PI3K signaling was critical for antibody production and expansion of inflammatory T cells. Further, we found that ICOS-PI3K signaling is important for maintenance of CIA in an antibody independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA suggesting a potential link between ICOS-PI3K signaling and glucose metabolism. Thus, we identified ICOS-PI3K axis as a key signaling pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.
•A conserved KKKY motif in the cytoplasmic tail of ICOS is necessary and sufficient for ICOS-mediated calcium flux.•ICOS-calcium and ICOS-PI3K signaling can be induced independently of each ...other.•ICOS activates both PLCγ1 and actin remodeling machineries to trigger release of calcium from the intracellular pool.
The inducible costimulator (ICOS) is a T cell costimulatory receptor that plays crucial roles in T cell differentiation and function. So far, ICOS has been shown to activate three signaling components: phosphoinositide 3-kinase (PI3K), intracellular calcium mobilization, and TANK binding kinase 1 (TBK1). By generating a knock-in strain of mice in which the ICOS gene is modified such that the ICOS-mediated PI3K pathway is selectively abrogated while the capacity of ICOS to mobilize intracellular calcium remains intact, we have shown that ICOS-mediated PI3K activation is required for some but not all T cell responses. This suggests that the ICOS-calcium signaling axis may explain some of the PI3K-independent ICOS functions. Further, a recent in vivo imaging study indicated that ICOS-dependent intracellular calcium flux facilitates cognate T cell-B cell interactions within the germinal center. However, how ICOS promotes TCR-mediated calcium flux has not been clear. Here we identified a membrane proximal motif in the cytoplasmic tail of ICOS that is essential for ICOS-assisted calcium signaling and demonstrate that ICOS can induce calcium flux independently of other signaling motifs. We also provide evidence that ICOS potentiates phospholipase Cγ1 (PLCγ1) activation to enhance calcium release from the intracellular pool. In parallel, acute ligation of ICOS without TCR co-engagement leads to activation of small GTPases, RhoA and Cdc42, consistent with the capacity of ICOS to induce actin remodeling. Importantly, interruption of actin dynamics during acute TCR or TCR-ICOS co-ligation severely impairs calcium flux in T cells even in the presence of activated PLCγ1. Thus, ICOS potentiates TCR-induced calcium flux by enhancing PLCγ1 activation and actin remodeling in a coordinated manner.
Staphylococcus aureus is a major human pathogen producing different types of toxins. Enterotoxin A (SEA) is the most common type among clinical and food-related strains. The aim of the present study ...was to examine the prevalence of sea in clinical isolates of S. aureus. Moreover, the correlation between sea producing strains and type of infection as well as resistance to antibiotics is also considered. 128 S. aureus isolates randomly collected from different clinical samples in Tehran University Hospitals from February 2008 to June 2008. Patients’ information including sex, infection type and the hospital where samples come from were recorded. The sea gene was observed among 60 (46.9%) of clinical isolates. There was a significant correlation between prevalence of sea gene and type of infection (P = 0.01). Furthermore, significant correlation was detected between the presence of sea gene and resistance to the most of antibiotics used in this study. The significant relationship between the type of infection and S. aureus isolates carrying sea indicates the interaction quality of the S. aureus pathogen and the host as well as the pathogenic role of S. aureus.
The serine/threonine protein kinase mammalian sterile 20-like kinase 1 (Mst1) is one of the key components of the evolutionarily conserved Hippo pathway that regulates multiple biological functions ...such as organ size, cell survival, proliferation, differentiation, and migration. Since the discovery of a primary immunodeficiency caused by MST1-null mutations in humans, substantial efforts have been made to characterize the function of MST1 in the immune system. So far, most studies have focused on the cellular immune responses and overall provided conflicting results regarding the role of MST1 in protective immunity. Counterintuitively, MST1-deficient patients show mildly elevated class-switched antibody titers. However, the quality of these antibodies and whether they provide long-lasting protective immunity has not been addressed in the previous studies. Thus, the role of MST1 in humoral immune responses remains largely unknown. Here, I hypothesized that the lack of protective antibodies may underlie immunodeficiency in humans as well as in mice. To test this idea, I analyzed antibody responses both under steady state and upon immunization using Mst1-deficient mouse models. Using a T-dependent immunization system to mimic a vaccination condition in humans, I demonstrated that young adult Mst1-deficient mice mounted early IgG1 responses to normal levels. However, antigen-specific IgG1 titers as well as bone marrow plasma cells were progressively lost similar to patients that failed to mount protective titers against protein vaccines administered at early ages of life. I provided evidence that this defect arises from the hematopoietic compartments as radio-resistant stromal tissues could support the long-lived antibody titers in bone marrow chimeras. Importantly, plasma cell production was clearly augmented at the early stages of germinal center reaction due to dysregulation of germinal center dynamics in the absence of Mst1. Thus, these findings indicate that overproduction of plasma cells and presumably accelerated turnover of bone marrow plasma cells may cause the premature loss of antigen-specific plasma cells in Mst1-deficient mice. My results suggest that long-lived high affinity humoral immune responses may be defective in MST1-deficienct patients. In contrast to IgG1 responses, Mst1-deficient mice raised and maintained elevated levels of high affinity IgE upon aging or immunization consistent with the hyper IgE titers observed in some of the patients. For the first time, here I provided evidence that hyper IgE can be6pathogenic since immunized Mst1-deficient mice suffered from anaphylactic shock when re-challenged with the immunizing antigens. Despite that fact that there are no reports of allergy in MST1-deficient patients, my results suggest that these patients may be prone to allergic reactions if exposed to certain antigens. Although we do not understand the underling mechanisms of IgE dysregulation in Mst1-deficiency, selective deletion of Mst1 in Foxp3+ Treg cells in our conditional knockout model demonstrated that Treg-specific Mst1-deficiency leads to pronounced hyper-IgE phenotypes. In addition, consistent with our expectations, my results demonstrated multi-organ autoimmune inflammation in Treg-specific Mst1-deficiency. Therefore, my work clearly indicates that Mst1 plays an important role in regulating IgE production through controlling the Treg cells. Taken together, my work illustrates the pivotal role of Mst1 in maintaining long-lived humoral immunity and controlling potentially pathogenic IgE contents in the mammalian immune system. Accordingly, prophylactic IgG replacement therapy may benefit MST1-deficient human patients. Further studies on Mst1-dependent immune regulatory mechanisms should help understand clinical aspects of the disease as well as fundamental biology of the immune system.
Staphylococcus aureus is a major human pathogen producing different types of toxins. Enterotoxin A (SEA) is the most common type among clinical and food-related strains. The aim of the present study ...was to examine the prevalence of sea in clinical isolates of S. aureus. Moreover, the correlation between sea producing strains and type of infection as well as resistance to antibiotics is also considered. 128 S. aureus isolates randomly collected from different clinical samples in Tehran University Hospitals from February 2008 to June 2008. Patients’ information including sex, infection type and the hospital where samples come from were recorded. The sea gene was observed among 60 (46.9%) of clinical isolates. There was a significant correlation between prevalence of sea gene and type of infection (P = 0.01). Furthermore, significant correlation was detected between the presence of sea gene and resistance to the most of antibiotics used in this study. The significant relationship between the type of infection and S. aureus isolates carrying sea indicates the interaction quality of the S. aureus pathogen and the host as well as the pathogenic role of S. aureus.
PDF
