Jeffrey Bluestone, Ph.D.
	Regulation of T-cell activation and development during immune responses
	Email: jbluest@diabetes.ucsf.edu Website:
Selected Publications | Complete Publications

The research in my laboratory concerns the fundamental events that regulate T-cell activation during immune responses to autoantigens and transplantation antigens. Our efforts have focused on understanding the basic processes that control T cell activation and tolerance. We hope that the insights gained from these studies will help in the development of novel therapies to be used in conjunction with stem cells to promote tissue and organ replacement.

Our efforts to modulate T cell activation have centered on understanding and altering the positive signals delivered by the antigen-specific T cell receptor and secondary, so-called co-stimulatory signals, or engaging the negative regulatory events such as CTLA-4, PD-1 and Notch that control T cell signal transduction. The studies focus on the yin/yang of the CD28/CTLA-4 pathways which are essential for a homeostatic T cell response. Blockade of CD28 interactions with its ligands, B7-1 and B7-2, induces long term tolerance in several different animal models. However, blockade of CTLA-4 interactions with the same B7 ligands exacerbates immunity. We have used soluble receptor antagonists, monoclonal antibodies and animals deficient in individual members of the CD28/CTLA-4/B7 pathways to define their individual roles in transplant rejection and autoimmunity. We have shown that CD28 co-stimulation blockade alters cell growth and survival, the differentiation state of the T cells and their ability to migrate into the inflammatory site. In critical studies, we showed that administration of a CD28 antagonist induces long-term, antigen-specific unresponsiveness in vivo in pancreatic islet transplant models in both mice and monkeys and regulates the progression of autoimmune diseases in mice. In sharp contrast, CTLA-4 engagement directly desensitizes T cell receptor phosphorylation and signaling leading to attenuation of T cell signaling and a shut down of autoimmune and transplantation responses through selective biochemical modifications of T cell receptor signaling, alteration of T cell differentiation and cytokine regulation. It is now clear that CTLA-4 engagement is essential in the development and maintenance of T cell tolerance in the autoimmune setting. Finally, we are interested in the negative regulation of immunity focused on the role of PD-1/PD-L1 pathways in the control of tissue specific tolerance.

Another part of the lab is focused on regulatory T cells, so called Tregs, and their involvement in autoimmunity and transplantation. We demonstrated that Tregs from autoimmune diabetes-prone mice protect via a TGF b -dependent pathway. These data provide an explanation for the tolerogenic effect of anti-CD3 antibodies and position them as the first example of a clinically applicable pharmacological stimulation of TGF- b producing regulatory CD4 + T cells. We have demonstrated that both the CTLA-4 and CD28 pathways control CD4+CD25+ regulatory T cells thus implicating these pathways in both the pathogenic and protective immune responses. Moreover, this work has led to the examination of a number of other co-stimulatory molecules (4-1BB, PD-1, ICOS and CD40L) in the development and progression of diabetes. We are using cutting edge tools, such as two-photon microscopy to dissect the cellular interactions that control immunity in vivo. Current efforts suggest that combination therapy, including the use of expanded Tregs, may be most effective in blocking diabetes in the NOD mouse model.

Thus, in summary, my lab has been involved in efforts to modify transplantation and autoimmune responses and understand the underlying mechanisms of T cell recognition of autoantigen. Using this information we hope to develop novel tolerogenic therapies that can be tested in man.

Selected Publications

Santamaria, P., Locksley, R.M., Krummel, M.F., Bluestone, J.A.: Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice, Nat. Immunol. 7:83-92, 2006.

Fife, B.T., Guleria, I., Gubbels-Bupp, M., Eagar, T.N., Tang, Q., Bour-Jordan, H. Yagita, H., Azuma, M., Sayegh, M.H., Bluestone, J.A. Insulin-induced remission in new onset NOD mice is maintained by the PD-1-PD-L1 pathway. J. Exp. Med. 203:2737-2747, 2006.

Herold, K.C., Gitelman, S.E., Masharani, U., Hagopian, W., Bisikirska, B., Donaldson, D., Rother, K., Diamond, B., Harlan, D.M., Bluestone, J.A.: A single course of anti-CD3 monoclonal antibody hOKT3?1(Ala-Ala) results in improvement in c-peptide responses and clinical parameters for at least 2 years after onset of Type 1 Diabetes. Diabetes 54:1763-9, 2005.

Fife, B.T., Griffin, M.D., Abbas, A.K., Locksley, R.M., Bluestone, J.A. Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist. J. Clin. Invest. 116:2252-2261, 2006.

Information last updated April 2007