Deficiency of CD4 T cells Contributes to Cardiac Fibrosis and Myocardial Dysfunction in T cell Specific S1P Receptor 1 Knockout Mice

Sphingosine 1‐phosphate (S1P) is a bioactive small lipid molecule involved in apoptosis, barrier formation and function, cytoskeleton rearrangement, vascular maturation, wound healing, cell trafficking, and other functions via five G protein‐coupled S1P receptors or/and intracellular lipid signaling. T cell S1P receptor 1 (S1P1) is responsible for mature T cell exit from thymus to the blood and periphery. Nevertheless, effects of T lymphocyte S1P1 on cardiac function and fibrosis remains incomplete understood. To this purpose, we generated T cell S1P1 knockout mice (TS1P1KO) by crossing S1P1 loxP / loxP mice with Lck‐Cre mice. Body weight (g) and glucose levels (mg/dl) in the blood were monitored. CD4 and CD8 T lymphocytes were counted by using flow cytometry. Pathological grading of heart histology was conducted in H&E stained sections. Masson Trichrome staining was utilized to evaluate cardiac fibrosis. Cardiac contractility was determined in Langendorff perfusion system. The TS1P1KO mice exhibited sustained deficiency of both CD4 and CD8 T cells in the blood compared with wild‐type littermate control. The TS1P1KO mouse heart featured an altered phenotype characterized by reduced cardiac contractility and increased cardiac fibrosis as well as morphological alteration, notably, loss of interstitial space between cardiac myocytes with thickening of vascular smooth muscle cells and perivascular edema compared with littermate vehicle mice. To explore the role of CD4 T cells in altered phenotype, naïve CD4 T cells were isolated by positive selection through MS column from CD4 magnetic microbeads‐labeled wild‐type littermate mouse splenocytes. Isolated CD4 T cells were adoptively transferred into TS1PKO mice intravenously at a dose of one million cells. TS1P1KO mice with reconstitution of CD4 T cells showed improved heart histology and less fibrosis as well as improved cardiac function compared with TS1P1KO mice without CD4 T cell transfer. In conclusion, deficiency of CD4 T cells in T cell S1P1 knockout mice contributes to cardiac fibrosis and myocardial dysfunction. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .