Browsing by Subject "Th17 cells"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection
    (Elsevier, 2021) Xu, Wenxi; Snell, Laura M.; Guo, Mengdi; Boukhaled, Giselle; Macleod, Bethany L.; Li, Ming; Tullius, Michael V.; Guidos, Cynthia J.; Tsao, Ming-Sound; Divangahi, Maziar; Horwitz, Marcus A.; Liu, Jun; Brooks, David G.; Microbiology and Immunology, School of Medicine
    Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.
  • Thumbnail Image
    Item
    STAT3 Signaling Heterogeneity Underlies Cytokine-Expressing Fate in Th17 Cultures
    (The American Association of Immunologists, 2023) Niese, Michelle L.; Glosson-Byers, Nicole; Moreira Serezani, Ana Paula; Alakhras, Nada S.; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    The polarization of naive Th cells into differentiated subsets in vitro was a powerful approach to define the development and function of Th cells in vivo. Th cell cultures identified cytokines that promote polarization and defined the phenotype and stability of differentiated cells. One of the limitations of this approach is the heterogeneity of the differentiated culture, essentially with regard to what proportion of the culture is secreting the hallmark cytokine of interest. This heterogeneity has always been puzzling because all cells in the culture have been exposed to identical culture conditions. We examined this phenomenon using an Il17f lineage-tracing allele (Cost, Cre on seventeen transcript) crossed to stop-flox Rosa-YFP (yellow fluorescent protein) mice. We found that less than half of the cells in a Th17 culture become lineage-positive during a differentiation culture and that it is primarily cells that are lineage-positive that produce cytokines when cultures are restimulated after differentiation. We sorted and analyzed YFP-positive and YFP-negative cells and found similar expression of many Th17 transcription factors, although YFP-negative cells had increased expression of other lineage-defining transcription factors. We observed that YFP-negative cells had diminished expression of Stat3 and Il6ra, as well as decreased STAT3 activation. YFP-negative cells transduced with active STAT3 had significant increases in IL-17A expression, without increases in Th17 transcription factors. Taken together, these data suggest that there is a threshold of STAT3 activation that is required for efficient Th17 differentiation, and that even in a culture of homogeneous naive T cells there is heterogeneity in the receipt of early cytokine signals.
  • Thumbnail Image
    Item
    Subcutaneous injection of adipose stromal cell-secretome improves renal function and reduces inflammation in established acute kidney injury
    (Springer Nature, 2024-04-24) Ullah, Md Mahbub; Collett, Jason A.; Monroe, Jacob C.; Traktuev, Dmitry; Coleman, Michael; March, Keith L.; Basile, David P.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Adipose stromal cells (ASC) are a form of mesenchymal stromal cells that elicit effects primarily via secreted factors, which may have advantages for the treatment of injury or disease. Several previous studies have demonstrated a protective role for MSC/ASC on mitigating acute kidney injury but whether ASC derived factors could hasten recovery from established injury has not been evaluated. Methods: We generated a concentrated secretome (CS) of human ASC under well-defined conditions and evaluated its ability to improve the recovery of renal function in a preclinical model of acute kidney injury (AKI) in rats. 24 h following bilateral ischemia/reperfusion (I/R), rats were randomized following determination of plasma creatinine into groups receiving vehicle -control or ASC-CS treatment by subcutaneous injection (2 mg protein/kg) and monitored for evaluation of renal function, structure and inflammation. Results: Renal function, assessed by plasma creatinine levels, recovered faster in ASC-CS treated rats vs vehicle. The most prominent difference between the ASC-CS treated vs vehicle was observed in rats with the most severe degree of initial injury (Pcr > 3.0 mg/dl 24 h post I/R), whereas rats with less severe injury (Pcr < 2.9 mg/dl) recovered quickly regardless of treatment. The quicker recovery of ASC-treated rats with severe injury was associated with less tissue damage, inflammation, and lower plasma angiopoietin 2. In vitro, ASC-CS attenuated the activation of the Th17 phenotype in lymphocytes isolated from injured kidneys. Conclusions: Taken together, these data suggest that ASC-CS represents a potent therapeutic option to improve established AKI.
  • Thumbnail Image
    Item
    The intrinsic expression of NLRP3 in Th17 cells promotes their protumor activity and conversion into Tregs
    (Springer Nature, 2025) Accogli, Théo; Hibos, Christophe; Milian, Lylou; Geindreau, Mannon; Richard, Corentin; Humblin, Etienne; Mary, Romain; Chevrier, Sandy; Jacquin, Elise; Bernard, Antoine; Chalmin, Fanny; Paul, Catherine; Ryffel, Berhard; Apetoh, Lionel; Boidot, Romain; Bruchard, Mélanie; Ghiringhelli, François; Vegran, Frédérique; Microbiology and Immunology, School of Medicine
    Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.