Lecture 14- Tregs

Lecture 14- Tregs - T-helper cell and regulatory T cell...

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Unformatted text preview: T-helper cell and regulatory T cell subsets Mechanisms of suppression by regulatory T cell subsets Regulatory T cell Lineage Specification by the Forkhead Transcription Factor Foxp3 Fontenot et al, Immunity , 2005 What the authors knew prior to this research: The human disease IPEX (X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy) is a fatal, multi-organ autoimmune disease, and the mutation maps to a transcription factor named Foxp3 A spontaneous mutation in mice ( scurfy ) with disease similar to IPEX also results from a defect in the murine Foxp3 gene CD4+CD25+ T cells have been show to exhibit regulatory (immune suppressive) activity, and express Foxp3 Foxp3 mutant mice display the scurfy phenotype, and ectopic expression of Foxp3 in non-regulatory T cells results in a gain of function to Tregs Question: are Foxp3+ cells a specific and distinct lineage of regulatory T cell Foxp3 is specifically expressed in CD4+CD25+ T cells and not in activated CD4+CD25- T cells Fontenot et al, NI , 2003 Deletion of Foxp3 by conditional knockout results in a systemic, lympho- proliferative disease. Animals first show scaly, inflamed skin and become moribund at the age of 4 weeks. Analysis of lymphoid tissue reveals splenomegaly, massive enlargement of lymph nodes, and lymphocyte infiltration into multiple organs. T cells recovered from animals display high levels of activation. Fontenot et al, NI , 2003 Foxp3 transduced by retrovirus into CD4+CD25- cells, then transferred into Rag-/- animals protected from lymphoproliferative disease- wasting (as shown by animal weight), colitis, and homeostatic expansion of CD8+ T cells Fontenot et al, NI , 2003 Foxp3-GFP mice are healthy and do not display the scurfy/Foxp3- phenotype A. GFP expression in lymph node lymphocytes B. GFP(Foxp3) is expressed in the nucleus (co-localize with DAPI) C. Foxp3-GFP mice display normal levels of CD4+CD25+ T cells Figure 2 D. CD4+CD25+ T cells from Foxp3 and Foxp3-GFP mice show similar in vitro suppression functions E. Since the foxp3 gene is on the X-chromosome, only 50% of CD4+CD25+ T cells should be GFP+ in female heterozygous animals. A statistically significant and equal distribution was observed in both thymocytes and lymph node cells Figure 2 A. Foxp3 expression is restricted to cells expressing TCR b, and not TCR gd or cells expressing NK1.1 (NK cells/NKT cells) Also, B cells, macrophages and dendritic cells do not express Foxp3,...
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This note was uploaded on 01/03/2012 for the course BI 144 taught by Professor List during the Fall '10 term at Caltech.

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Lecture 14- Tregs - T-helper cell and regulatory T cell...

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