Jian Zhang, M.D.

Research Summary

The research in my laboratory is focused upon molecular mechanisms of T cell activation and apoptosis and potential roles in autoimmunity.

Autoimmune diseases result from the failure of the immune system to develop tolerance to self-proteins. The signaling threshold of antigen receptors and costimulatory receptors determine immunity or tolerance to self-proteins. A major costimulatory receptor, CD28, is required for induction of autoimmunity in several mouse models. CD28 costimulation amplifies early and late TCR-mediated signaling events, and may lower the threshold needed for T cell activation. In support of this notion, our recent results have indicated that stimulation with higher doses of anti-CD3 partially overcomes defective T cell proliferation in CD28-/- mice. Further, we have shown that Cbl-b, an adaptor protein and ubiquitin ligase, can regulate the threshold for CD28-mediated T cell activation. Loss of Cbl-b uncouples the requirement for CD28 and CTLA-4 costimulation, indicating that Cbl-b is one of the key signaling molecules involved in both CD28- and CTLA-4-mediated T cell costimulation. We are currently trying to identify novel proteins regulated by Cbl-b, to evaluate whether and how Cbl-b regulates CD28-mediated formation of immunological synapse, and to investigate the potential role of Cbl-b in regulating CD28-dependent autoreactive T cell activation in autoimmune diseases.

Activation-induced cell death (AICD) results from repeated stimulation through the TCR, and is dependent upon the interaction between Fas and Fas ligand (FasL). Therefore, Fas-mediated AICD is an important mechanism for maintaining tolerance to self-antigens, such as those involved in autoimmune arthritis. My laboratory has studied the molecular mechanisms that underlie AICD and the potential role of AICD in autoimmune diseases. IL-4 can regulate T cell susceptibility to AICD via an IL-2-dependent mechanism. Currently, we are investigating how cytokines, especially IL-4, regulate AICD in autoimmune arthritis in vitro and in vivo. Understanding of the signaling mechanisms of Fas-mediated AICD will provide new therapeutic targets for designing novel agents to cure autoimmune diseases including autoimmune arthritis.

Selected Papers

Salojin K, Zhang J, Meagher C, Delovitch TL. (2000). ZAP-70 is essential for the T cell antigen receptor-induced plasma membrane targeting of SOS and Vav in T cells. J.Biol.Chem 275:5966.

Zhang J, Gao J-X, Salojin KV, Shao Q, Grattan M, Meagher C, Laird DW, Delovitch TL. (2000). The regulation of Fas ligand by p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase during activation-induced cell death in T cells. J.Exp.Med. 191:1017.

Gao J-X, Zhang J, Bergerot I, Bell D, Delovitch TL. (2000). XLCMTM: Preferential proliferation and differentiation of double-positive thymocytes into CD8+ single positive thymocytes in a novel cell culture medium. Cell. Immunol. 202:41.

Zhang J, Mikecz K, Finnegan A, Glant TT. (2000). Spontaneous thymocyte apoptosis is regulated by a mitochondrion-mediated signaling pathway. J. Immunol. 165:2970.

Zhang J, Salojin KV, Arreaza GA, Cameron M, Delovitch TL. (2001). CD28 costimulation restores T cell responsiveness in nonobese diabetic mice by overcoming deficiencies in Rac-1/p38 MAPK signaling and IL-2 and IL-4 gene transcription. Int. Immunol. 13:377.

Zhang J, Bardos T, Mikecz K, Finnegan A, Glant TT. (2001). Impaired Fas signaling pathway is involved in defective T cell apoptosis in autoimmune murine arthritis. J. Immunol. 166:4981.

Finnegan A, Doodes P, Grusby M, Kaplan C, O’Neal S, Eibel H, Koreny T, Czipri M, Mikecz K, Glant TT, Zhang J. (2002). IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J. Immunol. 169:3345.

Bárdos T, Zhang J, Mikecz K, David CS, GLANT TT. (2002). Mice lacking endogenous histocompatibility complex class II develop psoriatic arthritis at advanced age. Arthritis Rheum. 46:2465.

Bárdos T, Mikecz K, Finnegan A, Zhang J, Glant TT. (2002). T and B cell recovery in arthritis transferred to SCID mice: Antigen-specific activation is required for restoration of autopathogenic CD4+ Th1 cells in a syngeneic system. J. Immunol.:168:6013.

Zhang J, Bardos T, Li D-D, Gal I, Csaba V, Xu J, Mikecz K, Finnegan A, Lipkowitz S, Glant TT. (2002). Cutting Edge: Regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J. Immunol. 169:2236.

Vermes C, Jacobs JJ, Zhang J, Firneisz G, Roebuck KA, Glant TT. (2002). Shedding of the Interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts. J. Biol. Chem. 277:16879.

Finnegan A, Kaplan CD, Cao Y, Eibel H, Glant TT and Zhang J. (2002). Collagen-induced arthritis is exacerbated in IL-10-deficient mice. Arthritis Res and Ther 5:R18.

Zhang J, Bardos T, Shao Q, Tschopp J, Mikecz K, Glant TT, Finnegan A. (2003). IL-4 potentiates activated T cell apoptosis via an IL-2-dependent mechanism. J. Immunol. 170:3495.

Arreaza G, Salojin K, Yang W, Zhang J, Gill B, Mi QS, Gao J-X, Meagher C, Cameron M, Delovitch TL. (2003). Deficient activation and resistance to activation-induced apoptosis of CD8+ T cells is associated with defective peripheral tolerance in nonobese diabetic mice. Clin Immunol 107:103.

Bardos T, Czipri M, Vermes C, Finnegan A, Mikecz K, Zhang J. (2003). CD4+CD25+ immunoregulatory T cells may not be involved in controlling autoimmune arthritis. Arthritis Res Ther 5:R106.

Glant TT, Adarichev VA, Nesterovitch AB, Szanto S, Oswald JP, Jacobs JJ, Firneisz G, ZHANG J, Finnegan A, Mikecz K. (2004). Disease-associated qualitative and quantitative trail loci in proteoglycan-induced arthritis and collagen-induced arthritis. Am. J. Med. Sci. 327:188.

Zheng X, Gao J-X, Chang X, Wang Y, Liu Y, Wen J, Zhang H, Zhang J, Liu Y, Zheng P. (2004). B7-CD28 interaction promotes proliferation and survival but suppresses differentiation of CD4-CD8- T cells in the thymus. J. Immunol. 173:2253.

Li D-D, Gal I, Csaba V, Alegre ML, Chong ASF, Chen L, Shao Q, Xu X, Koreny T, Mikecz K, Finnegan A, Glant TT, ZHANG J. (2004). Cutting Edge: Cbl-b: One of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation. J. Immunol. 173: 7135.