Abstract: IL17 producing T helper lymphocytes (Th17 cells) are often recruited
at sites of tissue inflammation and participate in cell-mediated inflammatory reactions
that involve interactions with the vascular endothelium. These interactions are
quantitatively different from the Th1 T cell subset, and are highly dependent on
E-selectin. T cell expressed E-selectin ligands were described befor... read moree the existence of Th17
cells emerged, thus, their contribution to Th17 recruitment is unclear. One such ligand is
syaloglycoprotein CD43, a protein with other pleiotropic functions but with unknown roles
in Th17 cells. Chapter 3.1 of the present thesis dissertation tests the hypothesis that
Th17 cells use specific E-selectin ligands that differ from other T cell subsets, and
identifies CD43 as a major Th17 cell expressed E-selectin ligand in vitro and in vivo. We
combine real time videomicroscopy and adhesion experiments under flow conditions in vitro,
and the air pouch model of leukocyte recruitment as well as intravital microscopy of the
inflamed cremaster muscle in vivo. In Chapter 3.2, we test the hypothesis that CD43
regulates antigen specific Th17 cell recruitment to sites of autoimmune reactions, using
the mouse model of Experimental Autoimmune Encephalomyelitis (EAE). We find that CD43
regulates Th17 cell recruitment to the spinal cord in an E-selectin independent way, and
hypothesize that CD43 regulates Th17 cell adhesion to ICAM-1. We present evidence that CD43
regulates Th17 cell adhesion and apical migration on ICAM-1, as well as ICAM-1 dependent
transmigration in vitro. Lastly, in Chapter 3.3, we test the hypothesis that CD43
contributes to pathological cardiac remodeling and heart failure (HF), using the thoracic
aortic constriction model (TAC) in which both E-selectin and ICAM-1 are upregulated in the
heart. We demonstrate for the first time that CD43 contributes to T cell and monocyte
recruitment to the heart, cardiac fibrosis and systolic dysfunction. In summary, we report
several new roles for the sialoglycoprotein CD43, some of which are specific of Th17 cells,
and others more broad in the context of heart inflammation in vivo. Our results identify
new CD43 regulated pathways involved in Th17 cell recruitment and in inflammation
associated with cardiac dysfunction.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Immunology.
Advisor: Pilar Alcaide.
Committee: Mercio Perrin, Honorine Ward, and Thereza