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

Professor
Internal Medicine
Rheumatology

Cancer Biology Program
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:

Perry, J.S.A., Russler-Germain, E.V., Zhou, Y.W., Purtha, W., Cooper, M.L., Choi, J., Schroeder, M.A., Salazar, V., Egawa, T., Lee, B.C., Abumrad, N.A., Kim, B.S., Anderson, M.S., Dipersio, J.F., Hsieh, C.S. (2018). Transfer of cell-surface antigens by scavenger receptor CD36 promotes thymic regulatory T cell receptor repertoire development and allo-tolerance. Immunity, 48, 923-936.

Chai JN, Peng Y, Rengarajan S, Solomon BD, Ai TL, Shen Z, Perry JSA, Knoop KA, Tanoue T, Narushima S, Honda K, Elson CO, Newberry RD, Stappenbeck TS, Kau AL, Peterson DA, Fox JG, Hsieh CS. Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation (2017). Sci. Immunol. 2:pii: eaal5068

Solomon BD, Hsieh CS (2016) Antigen-Specific Development of Mucosal Foxp3+ RORgt+ T cells from Regulatory T cell Precursors. J. Immunol. 197, 3516-9.

Nustch K, Chai JN, Ai TL, Russler-Germain E, Feehley T, Nagler CR, Hsieh CS (2016) Rapid and efficient generation of regulatory T cells to commensal antigens in the periphery. Cell Reports, 16, 206-20.

Perry, J.S.A., Lio, C.W.J.,Kau, A.L., Nutsch, K., Yang, Z., Gordon, J.I., Murphy, K.M., & Hsieh, C.S. Distinct Contributions of Aire and Antigen-Presenting-Cell Subsets to the Generation of Self-Tolerance in the Thymus. Immunity, 2014: 41:414-26.

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.

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.

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

Last Updated: 7/27/2018 11:18:36 AM

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