|Division of Rheumatology, Department of Medicine
Associate Professor of Medicine, and
Alan A. and Edith L. Wolff Professor of Rheumatology
CSRB, Room 6610
Website | 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.
DBBS Graduate Program Affiliation