Appointments:

The research in my lab focuses on mechanisms of inactivation of T cells and T cell tolerance. We are interested in T cell receptors such as CTLA-4 and PD-1 that inhibit T cell responses as well as in the biochemical pathways in T cells that can be inhibited to achieve donor-specific tolerance in vivo in models of autoimmunity and transplantation.

T cells are activated through recognition of antigenic peptides by the T cell receptor concurrently to signals delivered by ligation of costimulatory receptors expressed on the cell surface. Upon activation, T cells upregulate receptors that can terminate T cell activation either through inducing cell-cycle arrest or apoptosis. CTLA-4 is one such molecule. We have found that CTLA4 is upregulated following T cell activation, and cycles from large intracellular pools to small regions on the surface of T lymphocyes. Surface CTLA4 is endocytosed following association with the clathrin adaptor AP50, but phosphorylation of a tyrosine in the cytoplasmic tail of CTLA4 allows retention on the cell surface. Different projects in the lab involve the search for molecules that may mediate the inhibitory signals delivered by CTLA4, as well as the effects of overexpression of CTLA-4 in T cells in models of autoimmunity and transplantation. For these projects, we are taking advantage of mice that have been made deficient in CTLA4 by gene targeting, and that we have crossed to T cell receptors of unique specificities, and of mice that over express CTLA-4 selectively in T cells.

In an effort to understand the biochemical pathways in T cells that are essential for the initiation of autoimmune diseases or of acute allograft rejection and that could potentially be targeted to achieve tolerance, we have focused on the importance of transcription factors. In particular, we are studying the role of NF-kB activation in T cells for the initiation of autoimmune diseases and acute allograft rejection. To this end, we are using mice with impaired NF-kB activation in T cells. These mice reject skin allografts but permanently accept cardiac allografts. Moreover, mice tolerant to cardiac allografts subsequently accept skin grafts from the same donor and show donor-specific tolerance. A major thrust in the laboratory is to characterize the mechanism of donor-specific tolerance in these animals as well as explore the role of NF-kB activation in T cells in the rejection of islet allografts and the initiation of autoimmune diseases such as diabetes.

Therefore, our current research focuses on the molecular and biochemical properties of T cell inhibitory receptors in vitro as well as on the roles of these receptors in transplantation and autoimmune diseases in vivo.

Selected Papers

Lin H, Rathmell JC, Gray GS, Thompson CB, Leiden JM, Alegre ML. (1998). CTLA4 blockade accelerates the acute rejection of cardiac allografts in CD28-deficient mice: CTLA4 can function independently of CD28. J. Exp. Med. 188:199.

Alegre ML, Shiels H, Thompson CB, Gajewski TG. (1998). Expression and function of CTLA4 in Th1 and Th2 cells. J. Immunol. 161:3347

Wissing M, Desalle F, Abramowica D, Willems F, Leo O, Goldman M, Alegre ML. (1999). The administration of an anti-CD3 mAb in mice differentially regulates the production of cytokines upon restimulation: implications for allogeneic skin graft survival. Transplantation, 68:677.

Alegre ML. (1999). Costimulatory molecules as targets for the induction of transplantation tolerance. Nephrology Dialysis Transplantation, 14:322.

Frauwirth KA, Alegre ML, Thompson CB. (2000). Induction of T cell anergy in the absence of CTLA-4/B7 interaction. J. Immunol., 164:2987.

Zhou P, Szot GL, Guo Z, Kim O, He G, Wang J, Grusby MJ, Newell KA, Thistlewaite JR, Blueston JA, Alegre ML. (2000). Role of STAT4 and STAT6 signaling in allograft rejection in wildtype and CD28 deficient mice. AM. J. Transplantation, 1:38.

Frauwirth KA, Alegre ML, Thompson CB. (2001). CTLA-4 is not required for induction of CD8+ T cell energy in vivo. J. Immunol., 167:4936.

Chin R, ZHou P, Alegre ML, FU YX. (2001). Confouncing factors complicate conclusions in aly model. Mature Medicine, 7:1165

Alegre ML, Frauwirth KA, Thompson, CB. T cell regulation by CD28 and CTLA-4. Nature Reviews in Immunology, 1:220

Harlin H, Podack E, Boothby M, Alegre ML. (2002). TCR-independent CD30 signaling selectivity induces IL-13 production via a TRAF/p38 MAPK-dependent mechanism. J. Immunol., 169:2451.

Harlin H, Hwang KW, Palucki D, Kim O, Thompson CB, Boothby M, Alegre ML. (2002). CTLA-4-engagement regulates NF-kB activation in vivo. Eur. J. Immunol., 32:2095.

Hwang KW, Sweatt WB, Brown IE, Blank C, Gajewski TF, Bluestone JA, Alegre ML. (2002). CUTTING EDGE: Targeted ligation of CTLA-4 in vivo by membrane-bound anti-CTLA-4 antibody prevents rejection of allogeneic cells. J. Immunol., 169:2451.

Zhou P, Hwant KW, Palucki DA, Guo Z, Boothby M, Newell KA, Alegre ML. (2003). Impaired NF-kB actiaveion permits tolerance to primary heart allografts and secondary skin grafts. Am. J. Transplant., 3:139.

Zhou P, Hwang KW, Palucki DA, Kim O, Newell KA, Fu YX, Alegre ML. (2003). Secondary lymphoid organs are important but not absolutely required for allograft responses. Am. J. Transplant., 3:359.

Fallarino F, Grohmann T, Hwang KW, Orabana C, Vacca C, Bianchi R, Belladonna ML, Rioretti MC, Alegre ML, Puccetti P. (2003). Modulation of tryptophan catabolism by regulatory T cells. Nature Immunology, 4:1206.

Subdhi SK, Zhou P, Yerian LM, Chin RK, Lo JC, Anders RA, Sun Y, Chen L, Wang Y, Alegre ML*, Fu YX*. (2004). Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection. J. Clin. Invest., 113:694. (*co-last authors)

O'Keefe JP, Blaine K, Alegre ML, Gajewski TF. (2004). Formation of a central supramolecular activation cluster is not required for activation of naive CD8+ Tcells. Proc. Natl. Acad. Sci. USA, 101:9351.

Hwang KW, Sweatt WB, Mashayekhi M, Palucki DA, Sattar H, Chuang E, Alegre ML. (2004). Transgenic expression of CTLA-4 controls lymphoproliferation in IL-2-deficient mice. J. Immunol., 173:5415.

Li D, Gal I, Vermes C, Alegre ML, Chong AS, CHen L, Shao Q, Adarichev V, Xu X, Koreny T, Mikeca 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.

Alegre ML. Featured Scientist in the American Society of Transplantation Newsletter, November-December 2004.

Alegre ML. (2004). Costimulatory pathways of T cell activation. Kidney Int., 64:1539.

Zhou P*, Balin SJ*, Mashayekhi M, Hwant KW, Palucki DA, Alegre ML. (2005). T cell depletion bot not T cell regulation plays a role in transplantation tolerance in mice with reduced T cell-intrinsic NF-kB activation. J. Immunol., 174:3447. (*co-first authors)

McNerney ME*, Lee KM*, Zhou P*, Molinero L, Mashayekhi M, Guzior D, Sattar H, Kuppireddi S, Wang CR, Kumar V*, Alegre ML*. (2006). Role of NK cellsubsets in cardiac allograft rejection. Am. J. Transplant., 6:505. (*co-first and co-last authors).

Chen L, Wang T, Zhou P, Ma L, Yin D, Shen J, Molinero L, Nozaki T, Phillips T, Uematsu S, Akira S, Wang CR, Fairchild RL, Alegre ML*, Chong A*. (2006). TLR engagement prevents transplantation tolerance. Am. J. Transplant., 6:2282. (co-last authors).

Fallarino F, Alegre ML. (2006). Mechanisms of CTLA-4-lg in tolerance induction. Current Pharmaceutical Design, 12:149.

Alegre ML, Najafian N. Targeting costimulatory molecules for the induction of transplantation tolerance. Current Molecular Medicine, in press.

Alegre ML, McNerney M. NK cell subsets in allograft rejection and tolerance. Current Opinions in Transplantation, in press.

Faculty and Research

Programs

Cancer Biology

Immunology

Microbiology

Molecular Metabolism
& Nutrition

Molecular Pathogenesis and
Molecular Medicine