Chyi-Song Hsieh, MD, PhD
Division of Rheumatology, Department of Medicine
Associate Professor of Medicine, and
Alan A. and Edith L. Wolff Professor of Rheumatology
CSRB, Room 6610
Pub Med Search
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.
Recently, we have begun to study the how regulatory T cells may contribute to tolerance to foreign bacteria that we are normally in contact with, such as the commensal bacteria in the colon. Our data suggests that regulatory T cells are efficiently generated from naïve T cells in response to commensal bacteria, thereby preserving tolerance to these foreign but benign antigens and preventing the development of colonic inflammation.
Current projects include: (1) understanding the mechanisms that direct the thymic development of natural regulatory T cells important for preserving self-tolerance and prevent autoimmunity; (2) understanding how antigen encounter in the colon results in regulatory, and not effector, generation from naïve T cells in order to maintain colonic tolerance; and (3) evaluating how regulatory T cell generation in the colon may be genetically or environmentally perturbed, resulting in colonic inflammation.
Lathrop, S.K., Bloom, S.M., Rao, S.M., Nutsch, K., Lio, C.-W., Santacruz, N., Peterson, D.A., Stappenbeck, T.S., and C.S. Hsieh. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011:
Lio, C.W., Dodson, L.F., Deppong, C.M., Hsieh, C.S., and J.M. Green. CD28 facilitates the generation of Foxp3– cytokine responsive regulatory T cell precursors. J. Immunol. 2010; 184:6007-6013.
Lee, H.M., and C.S. Hsieh. Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J. Immunol. 2009; 183:2261-2266.
Bautista, J.L., Lio, C.W.J., Lathrop, S.K., Forbush, K., Liang, Y., Luo, J., Rudensky, A.Y., and C.S. Hsieh. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 2009; 10:610-617.
Lathrop, S.K., Santacruz, N.A., Pham, D., Luo, J., and C.S. Hsieh. Antigen-specific peripheral shaping of the natural regulatory T cell population. J. Exp. Med. 2008; 205:3105-3117.
Lio, C.W., and Hsieh, C.S. A two-step process for thymic regulatory T cell development. Immunity 2008; 28:100-111.
Lee, H.M., Bautista, J.L., Scott-Browne, J., Mohan, J.F., and C.S. Hsieh. Tuning of thymic regulatory T cell selection to the self-reactive peripheral immune response. Immunity 2012:37:475-86.
Hsieh, C.S., Lee, H.M., and C.W. Lio. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 2012:12:157-67.
Ai TL, Solomon BD, Hsieh CS. T-cell selection and intestinal homeostasis. Immunol Rev. 2014 May;259:60-74.
DBBS Graduate Program Affiliation