Chyi-Song Hsieh, M.D., Ph.D.
Assistant Professor of Medicine
Adjunct Assistant Professor, Immunology

Office: Rm 6610 Clinical Science Research Building
Campus Box 8045

Office 314-362-2214

Lab 314-362-2266

Fax 314-454-1091
e-mail: chsieh@im.wustl.edu

Research Interests:
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) ongoing efforts to understand the T cell receptor repertoire of naturally arising CD25+ CD4+ regulatory T cells, important in preserving self-tolerance; (2) isolating T cell receptors from multiple tissues with the hypothesis that self-reactive T cells in those tissues will likely be specific for those tissue antigens; and (3) the study of changes in the T cell receptor repertoire in the sle1 congenic which exhibits a loss of tolerance to chromatin and are a model for systemic lupus erythematosis.

Selected References:

1. Hsieh, C.S., Liang, Y., Tyznik, A., Self, S.G., Liggett, D., and A.Y. Rudensky. 

Recognition of the peripheral self by naturally-arising CD25+ CD4+ T cell receptors.  Immunity 2004: 21:267-277.

2. Hsieh, C.S., Zheng, Y., Liang, Y., Fontenot, J.D., and A.Y. Rudensky.  An intersection between the self-reactive regulatory and non-regulatory T cell receptor repertoires.  Nat. Immunol. 2006: 7:401-410.

3. Lio, C.W., and Hsieh, C.S.  A two-step process for thymic regulatory T cell development.  Immunity, 2008; 28:100-111.