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Shyr-Te  Ju
Degree(s): Ph.D.
Graduate School: University of Illinois Medical Center at Chicago
Primary Appointment: Professor of Medicine, Nephrology
Research Interests:
Regulatory T Cells and Multi-Organ Autoimmune Disease

Email Address: sj8r@virginia.edu
Biomedical Sciences Graduate Program(s)
  • Microbiology, Immunology and Infectious Diseases
    • Research Description

    We are studying autoimmune inflammation controlled by the CD4+CD25+Foxp3+ regulatory T cells (Treg). Mice genetically deficient in Treg including Il2-/-, Il2r alpha-/- and Foxp3sf/Y (Sf) are used. The Sf mice in particular 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. However, many organs/tissues are spared from autoimmune attack. 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. 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 with respect to their organ/antigen specificity.

    A massive systemic expansion of CD8+ memory T (T M) cells and a remarkable increase in circulating IL-2 were observed only in Il2r alpha-/- mice but not in Il2-/- and Sf mice, although all three mutants are deficient in Treg. However, both phenotypes in Il2r alpha -/- mice were suppressed by the transfer of Treg. Treg-deficiency drives naive T cells to T M cells. In addition, high serum IL-2 was present in Il2r alpha -/- mice and was preferentially used by CD8 + T M cells through its abundant low-affinity IL-2R, resulting in systemic CD8 + T M cell dominance. We are studying the mechanism(s) accounting for high serum IL-2 in Il2r alpha -/- mice. One involves consumption due to lack of high affinity IL-2R and the other involves BLIMP-1 transcription factor which is a feedback control for IL-2 production and may be dysregulated in the absence of high affinity IL-2/IL-2 interaction.

    Mutation of the Foxp3 in Sf mice results in severe multi-organ autoimmune syndrome, and early death at 4 weeks old. However, Sf mice simultaneously bearing the Il2 -/- (Sf.Il2 (-/- ) or Fas lpr/lprgene (Sf.Faslpr/lpr) have extended lifespan despite totally lacking Treg, indicating a role of IL-2 and CD95 (Fas) signaling pathways in the multi-organ autoimmune syndrome beyond the Treg checkpoint. Importantly, the pattern of organ-specific autoimmune response of Sf.Il2-/- mice resembled Il2-/- mice whereas that of Sf.Faslpr/lpr was similar to Sf mice, indicating that the distinct and weakened autoimmune manifestation in Il2-/- mice was not caused by the residual Treg and that both Il2-/- and Faslpr/lpr genes prolong the lifespan of Sf mice but by different mechanisms. One of our goals is to understand how IL-2 regulates autoimmune inflammation in an organ-specific manner.

    Il2-/- or Il2r alpha-/- mice invariably develop inflammation in the submandibular gland (SMG) and salivation dysfunction. In contrast, the SMG of Sf mice were not inflamed. Moreover, Sf mice co-expressing Faslpr/lpr, Il2 -/- or Il2r alpha-/- gene remained free of inflammation in their SMG even though they lived significantly longer and contained autoimmune T cells capable of inducing inflammation in the SMG of Rag1-/- recipients. The SMG of Foxp3sf/Y mice was growth arrested before the stage when dominant sexual-dimorphic display of granular convoluted tubules (GCT) normally occurred, yet testosterone treatment restored GCT development but not inflammation. These observations indicate that Foxp3sf/Y inhibits SMG development and define a critical development stage that renders SMG resistance to inflammation induced by competent autoimmune T cells. We hypothesize that the expression of a critical antigen(s) (not associated with GCT development) is inhibited in Sf mice. One of the goals in this project is to identify the antigen(s) and define the specific autoimmune T cells.

    Selected Publications
  • 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. Epub: doi:10.1093/iniimm/dxn017.
  • 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.
  • Sharma R, Jarjour WN, Zheng L, Gaskin F, Fu SM, and Ju, S-T. Large functional repertoire of regulatory T-cell suppressible autoimmune T cells in scurfy mice. J. Autoimmunity. 2007. 29: 10-19.
  • Sharma R, Zheng L, Deshmukh US, Jarjour WN, Sung S-s, Fu SM, and Ju S-T. Cutting Edge: A regulatory T cell-dependent novel function of CD25 (IL-2Ralpha) controlling memory CD8+ T cell homeostais. J. Immunol. 2007. 178: 1251-1255.
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      Office Address: PO Box 800133, 
      Office Phone: +1 434-243-6358
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