DE NOVO EXPRESSION AND FUNCTION OF THE EPITHELIAL MUCIN MUC1 ON T CELLS
MUC1 has conventionally been studied as an epithelial cell surface molecule. Its glycosylation and expression change when those cells are transformed into adenocarcinomas. These changes have led to focus on MUC1 as a tumor antigen and also its role in adhesion to blood vessels and signaling within the tumor cell. The recent discovery that T cells also express MUC1 on their surface extends the physiological role of MUC1, with the possibility that functions observed in tumors may be reproduced on T cells.
Expression of MUC1 on T cells was first characterized in terms of timing, location and structure. T cells activated both in vivo and in vitro express MUC1. Expression in vitro is maintained over long time periods as the T cell population acquires the memory phenotype. Activated T cells induced to polarize by inflammatory conditions focus MUC1 expression to their leading edge, the sensory compartment of polarized T cells. Reactivity with glycosylation-sensitive antibodies and induction of glycosyltransferases indicates that the glycosylation of MUC1 on T cells is similar to that on normal epithelial cells.
A MUC1-negative T cell line was transfected with MUC1 cDNA and used as a model to investigate consequences of MUC1 expression on the T cell surface. Interaction of MUC1+ T cells with resting or activated endothelial cells revealed that MUC1 aids in adhesion under both normal and inflammatory conditions. Analysis of interactions with individual adhesion molecules demonstrated MUC1 specific enhancement of binding to ICAM-1 but inhibition of binding to E-selectin. Phosphorylation of the MUC1 intracytoplasmic tail is constitutive but decreases upon interaction with activated endothelium. MUC1 expression on T cells is also associated with differential phosphorylation of proteins in the molecular weight ranges of 39 kDa, ~80 kDa and 190 kDa, with the ~80 kDa band identified as beta-catenin.
While human T cells express MUC1 on their surface upon activation, this does not appear to be a characteristic of mouse T cells from the human MUC1 transgenic mouse model. However, as recent work indicates that mouse T cells express mouse Muc-1 after activation, human and mouse T cells may similarly depend on MUC1 for normal functioning.
Advisor:Olivera J. Finn, PhD; William Ridgway, MD; Penelope Morel, MD; Rebecca Hughey, PhD; JoAnne Flynn, PhD; Timothy M. Carlos, MD
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:09/12/2003