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 a new generation of tolerogenic drugs that will "turn off" selected parts of the immune system, leaving the disease-fighting capabilities intact.
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 and PD-1 that control T cell signal transduction. The CD28 studies have focused on defining a “genetic fingerprint” for the CD28 co-stimulatory pathway. The idea is that CD28 signaling leads to a unique set of up-regulated and down-regulated genes that leads to a differentiated T cell state. The studies in this arena include selective over-expression and knock-out of these genes to determine their affect of the signaling machinery of T cells in autoimmunity and tolerance.
The studies focus on the use of negative regulatory pathways to induce and control tolerance induction. Blockade of CTLA-4 interactions with the B7-1 but not B7-2 ligand and PD-1 ligation with PD-L1 but not PD-L2 ligand exacerbates immunity. We have shown that these pathways control both anergy induction and regulatory T cells function – altering the cell growth and survival, the differentiation state of the T cells and their ability to migrate into the inflammatory site. The model system for inducing tolerance in NOD depends on antigen-coupled fixed antigen-presenting cells as a robust and long-lived tolerogenic protocol that depends on both CTLA-4 and PD-1. Future studies include the use of two-photon microscopy and in vivo modeling in this tolerance setting to determine the precise roles of these negative regulatory pathways at different stages of immunity and 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 Foxp3+ 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. We are using cutting edge tools, such as two-photon microscopy and BAC transgenesis to dissect the cellular interactions that control immunity in vivo. For instance, we have developed a Foxp3-CRE NOD mouse strain that can be used to study the role of individual genes selectively expressed in Tregs. 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.
Louvet, C., Kabre, B.G., Davini, D.W., Martinier, N, Su, M.A., DeVoss, J.J., Rosenthal, W.L., Anderson, M.S., Bour-Jordan, H., and Bluestone, J.A. A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy J. Exp. Med. 206:507-14, 2009.
Tang, Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, and Bluestone JA. Central role of a defective IL-2 production in triggering islet autoimmune destruction. Immunity 28:687-97, 2008.
Putnam, A.L., Brusko, T.M., Lee, M.R., Liu, W., Szot, G.L., Ghosh, T., Atkinson, M.A., and Bluestone, J.A. Expansion of Human Regulatory T Cells from Patients with Type 1 Diabetes Diabetes 58:652-62, 2009.
Louvet, C., Szot, G.L., Lang, J., Lee, M.R., Martinier, N., Bollag, G., Zhu, S., Weiss, A., Bluestone, J.A. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A 105:18895-900, 2008.
Cano DA, Rulifson IC, Heiser PW, Swigart LB, Pelengaris S, German M, Evan GI, Hebrok M and Bluestone JA (Co-senior authors). Regulated b -cell regeneration in the adult mouse pancreas. Diabetes 57 : 958-66, 2008.
Bour-Jordan H, Salomon BL, Thompson HL, Santos R, Abbas AK and Bluestone JA. Constitutive expression of B7-1 on B cells uncovers autoimmunity towards the B cell compartment in the NOD mouse. J. Immunol. 179:1004-12, 2007.
Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt L, Bluestone JA, Sheppard D. Loss of integrin a v ß 8 on dendritic cells causes autoimmunity and colitis in mice. Nature 448:727-838, 2007.
Tang, Q., Adams , J.Y., Tooley, A.J., Bi, M., Fife , B.T., Serra, P., 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.