Abstract 104: Deletion Of Myd88 In T-Cells Worsens Pathology In A Mouse Model Of Non-Ischemic Heart Failure Through Enhanced T-Cell Survival And Effector Function:

Abstract

Background: Heart failure (HF) is a leading cause of death worldwide, associated with cardiac and systemic inflammation. However, no anti-inflammatory therapies have shown success thus far. Damage associated molecular patterns (DAMPs) released in the heart can activate myeloid cells to promote antigen presentation to T-cells, which infiltrate the heart and participate in adverse cardiac remodeling. DAMP signaling converges onto the adaptor protein “Myeloid differentiation primary response 88” (MyD88). DAMP receptors and MyD88 are also expressed in T-cells, but their role in T-cell activation is unclear, and is unknown in the context of HF. We hypothesized that T-cell recognition of DAMPs through MyD88 causes “bystander activation” of T-cells and contributes to cardiac pathology in HF. Methods and Results: We reconstituted Tcra -/- mice, normally protected from HF, with WT or Myd88 -/- Type 1 helper T-cells (Th1) in the onset of transaortic constriction (TAC), a well-established model of HF. Surprisingly, we found that mice given Myd88 -/- Th1 cells exhibited significantly higher levels of cardiac T-cell infiltration, more severe fibrosis, and lower fractional shortening than mice given WT Th1 cells. We found that WT and Myd88 -/- Th1 cells had similar levels of IFNγ and Tbx21 by intracellular staining and RT-qPCR, indicating that MyD88 does not alter Th1 differentiation. However, Myd88 -/- Th1 cells secreted higher levels of IL-2 and TNFα, suggesting enhanced proliferative and pro-inflammatory effector function. We performed viability studies using live cell microscopy and measuring propidium iodide incorporation in real time, as well as by flow cytometry, and found that Myd88 -/- Th1 cells have a survival advantage compared to WT Th1 cells. Moreover, we found that Myd88 -/- Th1 cells exhibited higher levels of adhesion to ICAM-1 and VCAM-1, protein ligands involved in T-cell recruitment, compared to WT Th1 cells when perfused under conditions of shear flow. Conclusion: Together, these data demonstrate that T-cell MyD88 limits T-cell mediated pathology in HF by modulating Th1 effector function, survival, and adhesion ability. We identify novel role for T-cell MyD88 in cardiac inflammation that may be modulated in HF.