Chyi-Song Hsieh, M.D., Ph.D.

Professor
Internal Medicine
Rheumatology

Immunology Program

  • 314-485-4485

  • 314-362-2266

  • 314-454-1091

  • 8045

  • 4940 Parkview Place, CSRB 6610

  • chsieh@wustl.edu

  • http://www.rheumatology.wustl.edu/faculty/hsieh.html

  • autoimmunity, immunology, lymphocyte, regulatory T cell, tolerance, mucosal immunology

  • Understanding T cell tolerance to self and non-self

Research Abstract:

During a T cell`s development, its antigen receptor (the T cell receptor) is generated through a process of somatic cell gene rearrangement. This highly diverse, randomly generated antigen receptor repertoire present in an individual`s T cell population ensures the recognition of a wide array of pathogens. However, the cost of this diversity is that some receptors will inevitably recognize self-antigens and potentially cause autoimmune disease. From a scientific perspective, the efficiency of the processes that control or eliminate these harmful T cells is quite amazing, evidenced by the relatively low frequency of autoimmune disease. However, this perspective is of little solace to those patients suffering from autoimmune disease, e.g. the 1% of the adult population that suffers from rheumatoid arthritis. The goal of my laboratory is to understand how self-reactive T cells are eliminated or controlled, thereby preserving tolerance to self and preventing autoimmunity, with the belief that this knowledge may eventually be utilized therapeutically in human disease. A major aim of our work is to study naturally arising T cell receptor repertoires developing in normal environments compared with genetically altered environments predisposed to autoimmune disease. However, the broad diversity of the normal T cell receptor repertoire precludes such analysis. To restrict the diversity of the T cell receptor repertoire to a manageable level, we use T cell receptor-beta chain transgenics to limit the variability in the T cell receptor repertoire to only the T cell receptor-alpha chain. This permits analysis of the T cell receptor repertoire by direct sequencing of the variable T cell receptor-alpha chains. We have accumulated a large database of T cell receptor sequences from normal CD4+ T cells, which will be a useful reference point for understanding autoimmune T cell repertoires. T cell receptors of interest can then be analyzed functionally for their antigen specificity and self-reactivity, as well as for their effects on T cell development.

Current projects include: (1) understanding the mechanisms that direct the thymic development of regulatory T cells important for preserving self-tolerance; (2) determining the antigen specificity of regulatory T cells generated in the periphery to commensal bacteria; and (3) evaluating how the immune system discriminates between harmful pathogenic bacteria versus helpful commensal species.

Selected Publications:

Lee HM, Bautista JL, Scott-Browne J, Mohan JF, and CS Hsieh. Tuning of thymic regulatory T cell selection to the self-reactive peripheral immune response. Immunity 2012: 37:475-86.

Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio C-W, Santacruz N, Peterson DA, Stappenbeck TS and Hsieh CS. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011 478:250-4.

Lio CW, Dodson LF, Deppong CM, Hsieh CS, Green JM. CD28 facilitates the generation of Foxp3– cytokine responsive regulatory T cell precursors. J. Immunol. 2010 184:6007-6013.

Lee HM, Hsieh CS. Rare development of Foxp3+ thymocytes at the CD4+CD8+ subset. J. Immunol. 2009 183:2261-2266.

Bautista JL, Lio CW, Lathrop SK, Forbush K, Liang Y, Luo J, Rudensky AY, Hsieh CS. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 2009 10:610-617.

Lathrop SK, Santacruz NA, Pham D, Luo J and Hsieh CS. Antigen-specific peripheral shaping of the natural regulatory T cell population. J. Exp. Med. 2008 205:3105-3117.

Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity 2008 28:100-11.

Last Updated: 7/29/2013 2:46:52 PM

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