Mucosal-associated invariant T (MAIT) cells are an unconventional subset of T cells that respond to vitamin B2 metabolites from a range of bacteria and fungi. We have previously reported that peripheral MAIT cells are activated during acute HIV infection (AHI) in a manner associated with markers of microbial translocation. Here, we characterized peripheral and colonic MAIT cells from people with HIV (PWH) during AHI and after ART initiated during AHI or chronic HIV infection (CHI) and investigated their interplay with the colonic microbiome. During AHI, both peripheral and colonic MAIT cells were activated and showed evidence of proliferation. MAIT cell activation in blood and colon were unrelated to viral load and to each other, suggesting compartmentalized responses. Colonic CD4 MAIT cells were reduced and their reduction was associated with viral load, suggesting a direct viral effect. In vitro experiments confirmed that CD4 MAIT cells are susceptible to HIV-1 infection. Finally, changes in colonic microbiome composition were evident already during AHI and were associated with peripheral blood MAIT cell activation and effector maturation. Thus, these findings indicate that viral replication and colonic microbiome perturbation are associated with distinct, compartment-specific components of the MAIT cell response during AHI.
Immune dysregulation is increasingly recognized as a key contributor to male infertility, yet the role of the efferent ductules in reproductive immune homeostasis remains unexplored. Located between the immune-privileged testis and the epididymis, efferent ductules are essential for male fertility by reabsorbing over 90% of testicular fluid and maintaining sperm in suspension through the coordinated activity of reabsorptive primary ciliated cells (RPCCs) and multiciliated cells (MCCs). Using complementary in vivo and in vitro approaches, we investigated the contribution of efferent ductule epithelial cells to innate immunity. In a mouse model of lipopolysaccharide (LPS)-induced epididymitis, efferent ductules displayed significant interstitial neutrophil infiltration and abnormal sperm accumulation, indicating disrupted local homeostasis. Both mouse and human epithelial cells expressed Toll-like receptor 4, supporting a role in pathogen sensing. Transcriptomic analyses showed MCCs enriched in cilia-related genes, while RPCCs preferentially expressed genes involved in signaling and inflammation. To further explore epithelial immune function, we developed 3D organoid models recapitulating key features of efferent ductules. Upon LPS stimulation, these organoids mounted a robust innate immune response, secreting cytokines, chemokines, and growth factors, consistent with in vivo observations. Together, these findings identify efferent ductule epithelial cells as an upstream immunological checkpoint and establish organoids as a valuable model to study efferent ductule epithelial cells function in male reproductive health.
EoE is an inflammatory condition characterised by tissue lesions and significant activation of immune cells in the oesophageal mucosa. Phenotypic and functional analyses in this study revealed widespread accumulation and activation of multiple immune cell types, with eosinophils showing the most notable expansion and activation. MAIT cells were the only activated T cell population associated with eosinophil activation, and this activation correlated with eosinophil infiltration in oesophageal tissue. Functional tests indicated that eosinophils increase MR1 expression in response to bacterial ligands and can present microbial antigens to and activate MAIT cells through an MR1- and TCR-dependent process, which, in turn, promotes cytokine release and further eosinophil activation. These findings reveal a previously unrecognised eosinophil-MAIT cell interaction that might enhance local immune responses by presenting microbial antigens that penetrate the lesioned mucosa and sustain inflammation in active EoE.
Early life is characterized by heightened susceptibility to respiratory pathogens, yet the immune mechanisms that predispose infants to infection remain poorly defined. Using an infant mouse model of Streptococcus pneumoniae (Spn) colonization, we identify an age-dependent delay in IL-17 A production that was associated with prolonged bacterial colonization in infant mice. Consistent with a critical role for this pathway, IL-17 receptor A (IL-17RA)-deficient infant mice exhibited persistent Spn colonization of the upper respiratory tract (URT). Transcriptomic profiling of the URT from Spn-colonized IL-17RA-deficient infant mice revealed an enrichment of antiviral responses compared to WT controls and included increased expression of the interferon-stimulated gene Cxcl10, a chemokine whose expression is positively associated with Spn carriage in humans. These results suggested that IL-17RA signaling constrains the interferon response during URT Spn colonization. WT infant mice exhibited progressively increased expression of Cxcl10 during Spn colonization and was dependent on type 1 interferon (IFNAR1) signaling and the pore forming bacterial toxin, pneumolysin. Genetic deletion of Ifnar1 or Cxcl10, including myeloid cell-specific deletion of Ifnar1, accelerated bacterial clearance in infant mice. In contrast, adult mice exhibited earlier induction of IL-17 A, minimal induction of Cxcl10 expression, and no alteration in bacterial clearance rates following Ifnar1 or Cxcl10 deficiency. Taken together, our results reveal a developmental window in which delayed IL-17 A production postpones the IL-17RA-dependent restraint of the type I interferon/CXCL10 axis, thereby prolonging pneumococcal carriage through impaired myeloid cell-mediated bacterial clearance.
