Accession Number : AD1013786

Title :   Mechanisms for Development and Function of Foxp3+ Regulatory T Cells

Descriptive Note : Technical Report

Corporate Author : Uniformed Services University Of The Health Sciences Bethesda United States

Personal Author(s) : Stoica,Cristina M

Full Text :

Report Date : 04 Apr 2008

Pagination or Media Count : 105

Abstract : Regulatory T cell mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. In this dissertation we present evidence that the marker gene of T reg cells (Foxp3) is expressed in a very early stage of thymic differentiation. By studying two different murine genetic backgrounds, we found several mechanisms leading to a differential thymic T reg development and function. While high rates of proliferation occurred in T-reg precursors with low Leptin receptor density, high rates of apoptosis occurred in T-reg precursors with elevated Bad, Caspase 3, and CD3 expression. Despite a differential T-reg thymic output, the size of peripheral CD4(+)25(hi)Foxp3(+) T-reg subset was normalized regardless the genetic background. Conversely, the T-reg suppressogenicity as tested in a model of autoimmune diabetes was directly correlated with the level of Foxp3 expression. A second important finding is that CD28 costimulation alone augmented, but did not induce de novo Foxp3 expression in T-reg thymic precursors. The CD28-upregulation of Foxp3 relied on mRNA stabilization, and required plasma membrane rafts integrity as well as a functional p56(lck) binding motif on the CD28 cytosolic tail. Noteworthy, the glycosphingolipids and cholesterol rafts components were unusual partitioned in T-reg precursors as compared with conventional T-cell precursors. The CD28-upregulation of Foxp3 was paralleled by an increase in thymic proliferation and in suppressogenicity of terminally differentiated CD4(+)25(hi) T-reg thymocytes. Extending the life span of Foxp3 transcripts in a rafts/p56lck manner represents a novel mechanism by which the CD28 co-receptor fosters the development and suppressogenicity of CD4(+)25(hi) T-reg precursors in the thymus.

Descriptors :   immune system , MEDICAL RESEARCH

Distribution Statement : APPROVED FOR PUBLIC RELEASE