Publication Date



Open access

Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Microbiology and Immunology (Medicine)

Date of Defense


First Committee Member

Eckhard R. Podack

Second Committee Member

Rebecca Adkins

Third Committee Member

Zhibin Chen

Fourth Committee Member

Robert Levy

Fifth Committee Member

Michael Kolber

Sixth Committee Member

Irena Pastar


Understanding how cytotoxic T cells (CTL) kill is of fundamental importance to the field of immunology. In the current model for how CTL kill target cells there is a critical dependence on lymphocyte-function associated antigen 1 (LFA-1, αLβ2) to tightly bind its ligand, intercellular adhesion molecule 1 (ICAM-1), following T cell receptor (TCR) recognition of cognate antigen (Dustin 2009). Recently, another member of the of integrin family, CD103 (integrin αE) has been characterized and data suggest that it may play an important role in killing ligand bearing targets (Feng, Wang et al. 2002; Gorfu, Rivera-Nieves et al. 2009). CD103 is expressed by lymphocytes of the mucosa, being found on a majority of intraepithelial lymphocytes in the small intestine (~90%)(Cepek, Shaw et al. 1994). Studies of pancreatic islet rejection after allo-transplantation have demonstrated that CD103+ effectors can be found at the site of tissue damage and that CD103-/- animals show delayed allograft rejection kinetics (Hadley, Bartlett et al. 1997; Feng, Wang et al. 2002). These data suggest that CD103 may play a role in the execution of CTL function in the mucosa precisely how remains unclear. Despite the understanding that retinoic acid (RA) and TGF-β are found abundantly in the intestinal mucosa, very little evidence exists with regard to their simultaneous effects on CD103. The studies here demonstrate that CD103 expression is rapidly induced by RA and TGF-β in the presence of antigen much more so than either of the two molecules alone. Additionally, previous vaccination studies have illustrated an efficient induction of CD103 on gp96 cross-primed OT-I cells at mucosal sites (Strbo, Pahwa et al. 2010). Results further show that antigen-dependent CTL activation in the presence of RA and TGF-β activate CD103 to participate in killing, which is blocked by antibodies that prevent binding to E-cadherin, CD103’s only known ligand. Moreover, we demonstrate that RA and TGF-β are capable of modulating the expression of granzymes. Notably, susceptibility to killing via CD103 activated cells can be augmented by ectopically expressing E-cadherin in targets that are not normally E-cadherin positive. Given that the only known ligand for CD103, E-cadherin, is highly expressed on the basolateral side of gut epithelium together with the relationship between CD103, RA and TGF-β, we speculate that CD103 may be a provider of immune surveillance function in the gut (Cirulli, Baetens et al. 1994; Le, Yap et al. 1999).


Immunology; Retinoic Acid; TGF-Beta; CD8 Lymphocytes; Perforin-1