Brief Description of Jiang's Research
The major theme of my research program is to understand how the immune system achieves self non-self discrimination, which remains a central conundrum in Immunology. I am particularly interested in studying the relationship of peripheral T cell regulation and self non-self discrimination, and translating the advanced intellectual concepts from my research to novel interventions for clinical applications.

In this regard, we initially identified a population of Qa-1 restricted CD8+ T cells, which mediate the resistance of autoimmune Experimental Allergic Encephalomyelitis (EAE) induced by the first episode of the disease. More severe symptoms of EAE develop, in a much less controllable fashion, during the relapse in CD8 knock out mice or the re-induction of EAE in Qa-1 knock out mice, indicating that Qa-1 restricted CD8+ T cells play an important role in maintaining peripheral self-tolerance.

During the past several years, we further proposed and tested an “Avidity Model of Peripheral T Cell Regulation” in which self non-self discrimination can be achieved in the periphery by the Qa-1 restricted CD8+ T cells that selectively down-regulate intermediate avidity T cells to both self and foreign antigens. Because the peripheral self-reactive T cell repertoire is devoid of high avidity T cells compared with foreign-reactive repertoire due to thymic negative selection, the selective down-regulation of intermediate but not high avidity T cells enables the immune system to suppress autoimmunity without damaging the on going immune response to foreign pathogens, a functional status of self non-self discrimination.

Recently, our study further demonstrated that a heat shock peptide (Hsp60sp), coupled with the MHC class Ib molecule Qa-1, is a surrogate target structure, preferentially expressed at a higher level on the intermediate avidity T cells and specifically recognized by the Qa-1 restricted CD8+ T cells. Thus, perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to discriminate self from non-self by a simple and unified mechanism of selective down-regulation of intermediate avidity T cells. The biological significance of this concept was demonstrated by the evidence that regulatory CD8+ T cells, specifically induced by and down-regulate Qa-1/Hsp60sp expressing cells, cross-protected animals from either autoimmune Experimental Allergic Encephalomyelitis or Type 1 Diabetes without damaging the ongoing immune response to foreign antigens. “Cross-protection” occurs because potentially pathogenic self-reactive T cells included in the pool of intermediate avidity T cells are capable of preferentially expressing common surrogate target structures on their surface to be subject to the down-regulation by the Qa-1 restricted CD8+ T cells, regardless of which antigens the target T cells are triggered by. The studies thus suggested that the immune system discriminates self from non-self, during adaptive immunity, not by recognizing the structural differences between self versus foreign antigens, but by perceiving the avidity of T cell activation.

Our studies present evidence for a nascent paradigm-shifting scientific theory in the field of immune regulation. If proven correct, the conceptual framework of the “Avidity Model” may open a new era of modern immunology and profoundly change the way that we deal with immunologically relevant clinical problems in general. For example, identification of the regulatory mechanisms, that function to discriminate self from non-self, would lead to new possibilities of novel clinical interventions to prevent and treat autoimmune diseases without damaging the normal on going anti-infection and anti-tumor immunity, which is the major side-affect of the currently used immuno-therapeutic drugs. In addition, the specificity of the regulation is not at the level of the antigens that activate the target T cells, control of auto-immune diseases could thus be achieved independent of the knowledge of the particular self-antigens involved, in any given auto-immune disease, that are largely undetermined at the present time. Unlike any other known peripheral regulatory mechanisms that function by controlling the magnitude and class of immune responses, Qa-1/HLA-E restricted CD8+ T cell mediated regulatory pathway represents the only currently identified peripheral mechanism that the immune system evolved to complete self non-self discrimination that is achieved, imperfectly, by thymic negative selection, in order to maintain self-tolerance. In this regard, manipulation of the common target structures recognized by Qa-1 restricted CD8+ T cells could be a basis for potential therapeutic interventions to specifically enhance or block this regulatory pathway in vivo. The potential application of such interventions in man is based on the evidence that the human homologue of Qa-1, HLA-E, can function as a restricting element for human regulatory CD8+ T cells.

Selected key publications:

Jiang, H., Zhang, S-L., and Pernis, B.  1992.  Role of CD8+ T Cells in murine experimental allergic endephalomyelitis. Science 256:1213-1215.

Jiang, H., Ware, R., Stall, A., Flaherty, L., Chess, L., and Pernis, B. 1995. Murine CD8+ T cells that Specifically Delete Autologous CD4+ T Cells Expressing Vb8 TCR: A Role of the Qa-1 Molecule. Immunity 2:185-194.

Ware, R., Jiang, H., Braunstein, N., Kent, J., Wiener, E., Pernis, B., and Chess, L. 1995. Human CD8+ T Lymphocyte Clones Specific for T Cell Receptor Vb Families Expressed on Autologous CD4+ T Cells. Immunity 2:177-184.

Jiang, H., Kashleva, H., Xu, L., Forman, J., Flaherty, L., Pernis, B., Braunstein, N., and Chess, L. 1998. T Cell Vaccination Induces TCR Vb Specific, Qa-1 Restricted Regulatory CD8+ T cells. Proceedings of the National Academy of Sciences 95:4533-4537.

Jiang, H. and Chess, L. 2000. The Specific Regulation of Immune Responses by CD8+ T Cells Restricted by the MHC Class lb Molecule, Qa-1. Annual Review of Immunology 18:185-216.

Jiang, H., Braunstein, N., Yu, B., Winchester, R., and Chess, L. 2001. CD8+ T Cells Control the TH Phenotype of MBP Reactive CD4+ T Cells in EAE Mice. Proceedings of the National Academy of Sciences 98:6301-6306.

Jianfeng, L.,Goldstein, I., Glickman, E., Jiang, H, and Chess, L. 2001. Induction of TCR Vb-Specific CD8+ CTLs by TCR Vb-Derived Peptides Bound to HLA-E. Journal of Immunology 167:3800-3808.

Jiang, H., Curran, S., Ruiz-Vazquez, E., Liang, B., Winchester, R., and Chess, L. 2003. Regulatory CD8+ T Cells Fine Tune the MBP Reactive TCR Vb Repertoire during EAE. Proceedings of the National Academy of Sciences 100(14):8378-8383.

S. Yan, Z. Wu, H. Zhang, G. Furtado, C. Brown, A. Stern, J. LaFaille, L. Chess, D. Stern, and H. Jiang. 2003. Suppression of Experimental Autoimmune Encephalitis by Selective Blockade of Encephalitogenic T-Cell Infiltration of the Central Nervous System. Nature Medicine 9:287-295.

Jiang, H. and Chess, L.  2004.  An Integrated Model of Immunoregulation Mediated by Regulatory T Cell Subsets.  Advances in Immunology 83:253-288.

Chess, L., and Jiang, H. 2004. Resurrecting CD8+ Suppressor T Cells. Nature Immunology 5:469.

Jiang, H. and Chess, L. 2004. An integrated view of suppressor T cell subsets in immunoregulation. J. Clin. Invest. 114 (9): 1198-1208.

Jiang, H. 2005. The Qa-1 Dependent CD8+ T Cell Mediated Regulatory Pathway. Cel Mol Immunol.2 (3): 161-167.

Jiang, H., Y. Wu, B. Liang, Z. Zheng, G. Tang, J. Kanellopoulos, M. Soloski, R. Winchester, I. Goldstein, and L. Chess. 2005. An Affinity/Avidity Model of Peripheral T Cell Regulation. J. Clin. Invest 115(2): 302-312.

Jiang, H. and Chess, L. 2006. Immune Response Regulated by T Cells. New England J. of Med. 354 (11): 1166-1176.

Chen W., L. Zhang, B. Liang, Li J. L. Chess and H. Jiang. 2007. Perceiving the Avidity of T Cell Activation Can Be Translated into Peripheral T Cell Regulation. Proceedings of the National Academy of Sciences 104(51): 20472-20477.

Jiang, H. and Chess, L. 2008. The Qa-1/HLA-E Restricted Regulatory CD8+ T Cells And Self Non-self Discrimination: An Essay for Peripheral T Cell Regulation. Human Immunology 69: 721-727.

Wu Y., Z. Zheng, Y. Jiang, L. Chess and H. Jiang. 2009. The Specificity Of T Cell Regulation That Enables Self Non-Self Discrimination In The Periphery. 106(2): 534-539
Proceedings of the National Academy of Sciences

Jiang, H. and Chess, L. 2009. How the Immune System Achieves Self Non-self Discrimination During Adaptive Immunity. Advances in Immunology 102(2): 94-133.