Despite the existing association of gut dysbiosis and T cell inflammation in heart failure (HF), whether and how gut microbes contribute to T cell immune responses, cardiac fibrosis and dysfunction in HF remains largely unexplored. Our objective was to investigate whether gut dysbiosis is induced by cardiac pressure overload, and its effect in T cell activation, adverse cardiac remodeling, and cardiac dysfunction. We used 16S rRNA sequencing of fecal samples and discovered that cardiac pressure overload-induced by transverse aortic constriction (TAC) results in gut dysbiosis, characterized by a reduction of tryptophan and short-chain fatty acids producing bacteria in WT mice, but not in T cell-deficient mice ( Tcra −/- ) mice. These changes did not result in T cell activation in the gut or gut barrier disruption. Strikingly, microbiota depletion in WT mice resulted in decreased heart T cell infiltration, decreased cardiac fibrosis, and protection from systolic dysfunction in response to TAC. Spontaneous reconstitution of the microbiota partially reversed these effects. We observed decreased cardiac expression of the Aryl hydrocarbon receptor (AhR) and enzymes associated with tryptophan metabolism in WT mice, but not in Tcra −/- mice, or in mice depleted of the microbiota. These findings demonstrate that cardiac pressure overload induced gut dysbiosis and T cell immune responses contribute to adverse cardiac remodeling, and identify the potential contribution of tryptophan metabolites and the AhR to protection from adverse cardiac remodeling and systolic dysfunction in HF.

recognizes early career investigators with demonstrated excellence as an investigator with recently established or emerging independence and with a research focus leading to an improved understanding of the conceptual basis of disease.

The stimulator of interferon genes 1 protein senses cyclic di-nucleotides released in response to double stranded DNA, and functions as an adaptor molecule for type I interferon (IFNI) signaling by activating IFNI stimulated genes (ISG). We found impaired T cell infiltration into the peritoneum in response to TNFα in global and EC-specific STING-/-mice and discovered that T cell transendothelial migration (TEM) across mouse and human endothelial cells (EC) deficient in STING was strikingly reduced compared to control EC, whereas T cells adhesion was not impaired. STING-/-T cells showed no defect in TEM or adhesion to EC, or immobilized endothelial cell expressed molecules ICAM1 and VCAM1 compared to WT T cells.Mechanistically, CXCL10, an ISG and a chemoattractant for T cells, was dramatically reduced in TNFα-stimulated STING-/-EC and genetic loss or pharmacologic antagonism of IFN-type I interferon receptor (IFNAR) pathway reduced T cell TEM. Our data demonstrate a central role for EC STING during T cell TEM that is dependent on the ISG CXCL10 and on IFNI-IFNAR signaling.

Summary T helper type 17 lymphocytes (Th17 cells) infiltrate the central nervous system (CNS), induce inflammation and demyelination and play a pivotal role in the pathogenesis of multiple sclerosis. Sialomucin CD43 is highly expressed in Th17 cells and mediates adhesion to endothelial selectin (E‐selectin), an initiating step in Th17 cell recruitment to sites of inflammation. CD43−/− mice have impaired Th17 cell recruitment to the CNS and are protected from experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. However, E‐selectin is dispensable for the development of EAE, in contrast to intercellular and vascular cell adhesion molecules (ICAM‐1 and VCAM‐1). We report that CD43−/− mice have decreased demyelination and T‐cell infiltration, but similar up‐regulation of ICAM‐1 and VCAM‐1 in the spinal cord, compared with wild‐type (WT) mice, at the initiation of EAE. CD43−/− Th17 cells have impaired adhesion to ICAM‐1 under flow conditions in vitro, despite having similar expression of LFA‐1, the main T‐cell ligand for ICAM‐1, as WT Th17 cells. Regardless of the route of integrin activation, CD43−/− Th17 cell firm arrest on ICAM‐1 was comparable to that of WT Th17 cells, but CD43−/− Th17 cells failed to optimally apically migrate on immobilized ICAM‐1‐coated coverslips and endothelial cells, and to transmigrate under shear flow conditions in an ICAM‐1‐dependent manner. Collectively, these findings unveil novel roles for CD43, facilitating adhesion of Th17 cells to ICAM‐1 and modulating apical and transendothelial migration, as mechanisms potentially responsible for Th17 cell recruitment to sites of inflammation such as the CNS.