Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
Research Description
We are studying autoimmune inflammation controlled by the CD4+CD25+Foxp3+ regulatory T cells (Treg). The Scurfy (Sf) mice are totally devoid of Treg and display the X-linked IPEX (Immune dysregulation, Poly-endocrinopathy, enteropathy, X-linked) syndrome characteristics of patients bearing mutations in the Foxp3 gene. Sf mice die at 4 weeks after birth with severe multi-organ autoimmune inflammation. Inflamed organs include skin, ear, tail, lung, liver, and kidney. Interestingly, Sf mice contain dormant autoimmune T cells capable of transferring new diseases such as sialoadenitis, dacryoadenitis, pancreatitis, gastritis, intestinal inflammation, colitis, and myositis in Rag1-/- recipients. Moreover, transfer of the multiple organ autoimmune diseases could be suppressed by Treg, mediated by inhibiting autoimmune T-cell expansion. Additional autoimmune inflammation, particularly those involved in male reproductive organs was observed by breeding Faslpr/lpr mutant gene into Sf mice that prolonged the lifespan beyond adult age. Our study shows a large repertoire of autoimmune lymphocytes against various organs/tissues in Sf mice as well as Treg in B6 mice capable of suppressing the expansion of these autoimmune lymphocytes. My goal for the next few years is to characterize the autoimmune and Treg repertoires and the mechanisms of organ-specific autoimmune inflammation development.
Project 1: Study of regulatory T cell repertoire and Foxp3 regulation in novel regulatory T cell hybridomas (Treg-hyb). We have now successfully generated cloned Treg-hyb using T cells of DO11.10 TCR transgenic (Tg) mice that bear the Foxp3-GFP knock-in gene. Treg-hyb expressed undetectable or very low Foxp3-GFP which could be strongly induced by cognate Ag OVA323-339 presented by Rag2-/- spleen cells and in the presence of rIL-2 and rTGF-b1. Rag2-/- spleen cells alone induced Foxp3-GFP expression, albeit 30 times less efficient. The induction, mediated by soluble factors, was highly specific because other Treg-associated markers were not affected. We identified rIL-6, rIL-9, rIL-27 out of 53 recombinant cytokines tested, and a <5-kd soluble factor from Rag2-/- spleen cells, as Foxp3-inducing factors. A common signaling component of these cytokines is STAT3 which is activated by the GP130 of IL-6R and IL-27R and by IL-9R that pairs with the common gamma chain. Treg-hyb technology can be used to address the self-reactivity issue of Treg based on classical T/Ag-APC interaction and to uncover novel pathways and mediators for Foxp3 induction.
Project 2: IL-2 is a mater regulator of receptors for CD4+ T cell trafficking and retention. Scurfy (Sf) mice (foxp3Sf/Y) totally lack regulatory T cells and develop multi-organ inflammation in which skin, lungs and liver are the more severely affected organs. Breeding Il2-/- gene into Sf mice protects the double mutant Sf.Il2-/- mice for life against skin and lung inflammation but the liver remains inflamed. Microarray analysis of the CD4+ T cells between Sf and B6 control indicates that chemokine receptors and Th2 lymphokines that are critical to peripheral organ inflammation are the highest regulated gene products. Interestingly, microarray analysis of the CD4+ T cells between Sf and Sf.Il2-/- mice revealed differentially regulated genes for chemokine receptors but not Th2 lymphokines. How IL-2 selectively regulates a specific set of chemokine receptors and how much each of the chemokine receptors contribute to skin and lung inflammation is being investigated.
Selected Publications
Sharma R, Sung SSJ, Abaya CE, Ju ACY, Fu SM, and Ju S-T. IL-2 regulates CD103 expression on CD4+ T cells in Scurfy mice that display both CD103-dependent and independent cutaneous and mucosal inflammation. 2009. J. Immunol. 183: 1065-1073.
Sharma R, Ju ACY, Kung JT, Fu SM and Ju S-T. Rapid and selective expansion of non-clonotypic T cells in regulatory T cell-deficient, foreign antigen-specific TCR transgenic scurfy mice: Antigen-dependent expansion and TCR analysis. J. Immunol. 2008. 181: 6934-6941.
Zheng L, Sharma R, Kung JT, Deshmukh US, Jarjour WN, Fu SM, and Ju S-T. Pervasive and stochastic changes in the TCR repertoire of regulatory T cell-deficient mice. Int. Immunol. 2008. 20: 517–523.
Zheng L, Sharma R, Gaskin F, Fu SM, and Ju S-T. A novel role of IL-2 in organ-specific autoimmune inflammation beyond regulatory T-cell checkpoint: Both IL-2 knockout and Fas mutation prolong lifespan of scurfy mice but by different mechanisms. J. Immunol. 2007. 179: 8035-8041.
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