Thomas R. Malek, Ph.D.

Professor and Vice Chair of Immunology and Microbiology
Room 3119, Rosenstiel Medical Sciences Building
1600 NW 10th Avenue
Telephone: 305-243-5626
Lab: 305-243-5627
Fax: 305-243-6903
email: tmalek@med.miami.edu

Research Interests:

Cytokine receptor regulation of T lymphocyte development, activation, and memory; T regulatory cells in suppression of autoimmunity.

One major interest in the lab is to ascertain how signaling through the IL-2 receptor controls the development of CD4+ CD25+ T regulatory cells. We are also investigating the specificity and suppressive activity of alloantigen-primed T regulatory cells in models of autoimmune disease and organ transplantation. In vitro and in vivo models systems have been developed that allow a direct analysis of the cell fate decision by activated CD8+ T cells to commit as effector or memory T cells. Here we evaluate the role of IL-2, IL-7 and IL-15 and their down-stream signaling pathways as well as antigen in this process. We are specially interested in how tumor-associated antigen effects the development of memory cells from effector CTL as effective tumor immunity should result in production of a potent T memory response.

Current Research Projects:

Immunobiology of T regulatory cells.
The action of CD4+CD25+ T regulatory (Treg) cells represents a major mechanism to inhibit self-reactivity by suppressing autoreactive mature peripheral T cells that have escaped thymic negative selection. In spite of the ready ability to demonstrate this immunological phenomenon, comparatively little is known concerning the factors controlling Treg cell development, specificity, homeostasis, and function. Recently, our laboratory established one important principle concerning Treg cells, namely that IL-2 is essential for their development. Importantly, we showed that the adoptive transfer of CD4+CD25+Treg cells prevented the onset of the rapid and lethal autoimmune disease in IL-2Rβ-/- mice that was accompanied by substantial expansion, followed by long-term stable engraftment, using syngeneic or fully allogeneic donor Treg cells. The efficacy of allogeneic Tregs cells to prevent autoimmunity is of considerable practical value in developing strategies to utilize Treg cells in adoptive immunotherapy. We have found that many Treg cells are specific for allogeneic MHC, as these cells have been selected to expand and survive in MHC-mismatched recipient mice. In principle, therefore, the TCR specificity is defined for these Treg cells, i.e. alloreactive to MHC class II. Thus, along with characterizing the immunosuppressive properties of allogeneic Tregs cells, a major objective of this project is to utilize this and other model systems to investigate the specificity and diversity of the TCR as it relates to Treg cell homeostasis and tolerance to alloantigens.

The IL-2 receptor in T regulatory cell development.
The process by which Treg cells develop within the thymus is poorly understood. Our past work established that thymic expression of a functional IL-2R was one critical step for the thymic production of Treg cells. A key role of IL-2 for Treg cells is not just limited to the thymus as we further showed that the IL-2/IL-2R interaction was essential for extensive expansion of Treg cells in neonatal lymph nodes, leading to a normal complement of these cells in secondary lymphoid tissue. Given the important role for Treg cells in T cell tolerance, understanding the basis by which this T cell subset develops may shed light on the basis of autoimmune disease and facilitate application of these cells in clinical situations, from autoimmunity, to organ transplantation, and tumor immunity. In this regard, a number of important unanswered questions remain concerning the contribution of IL-2 to the production of Treg cells. These include: What are the consequences of IL-2 signaling for Treg cells within the thymus? Is IL-2 just a growth/survival factor or does it more broadly program Treg cells? Is the role of IL-2 similar in both the thymus and in secondary lymphoid tissue? What are the signaling requirements through the IL-2R for the production of Treg cells? What is the cellular source for IL-2 for Treg cells? The major objective of this project is to answer these questions and hence establish a much more detailed understanding concerning the contribution of IL-2 in the developmental production of Treg cells.

T cell immunity and cytokine receptor signaling.
The processes by which activated T cells develop into armed effector cells or ultimately persist as a long-lived memory cells are becoming better understood. Signal transduction through the IL-2R prominently contributes to these processes. IL-2 promotes optimal T effector responses and is essential for extensive effector cell proliferation and development in vitro. Furthermore, recent data suggest that IL-2 signaling during the primary response may be critical for memory CD8 T cells to proliferate and mediate effector activity upon a recall antigenic challenge. Nevertheless, the molecular mechanism that regulates the effector versus memory cell fate decision and the precise contribution by IL-2 to these processes remains largely undefined. We have developed a culture system that models effector and memory T cell development and characterized unique mouse models with a selective defect in IL-2R signals by peripheral T cells. These experimental tools are especially useful for direct analysis of IL-2-dependent molecular events controlling effector versus memory development. Utilizing these, we uncovered a novel auto-regulatory loop in which IL-2 inhibits its own production that may be an important checkpoint for effector and/or memory production. This inhibitory pathway depends upon the transcriptional repressor Blimp-1.Thus, the major objectives for this project are to establish the molecular basis by which IL-2 signaling regulates effector and memory cell production and to ascertain the biological relevance of Blimp-1-dependent regulation of activated T cells.

Recent publications:

Gong, D. and Malek, T.R. Blimp-1 is expressed by activated T cells and inhibits IL-2 production. J. Immunol. 178: 242-252, 2007.

Bayer, A. L., Yu, A. and Malek, T. R. Function of the IL-2R for thymic and peripheral CD4+ CD25+ Foxp3+ T regulatory cells. J. Immunol. 178:4062-4071, 2007.

Yu, A. and Malek, T. R. Selective availability of lL-2 is a major determinant controlling the production of CD4+CD25+ Foxp3+ T regulatory cells. J. Immunol: 177:5115-5121, 2006.

Jin, H. and Malek, T. R. Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21 J. Leuk. Biol. 80:1416-1423, 2006.

Adeegbe, D.. Bayer, A. L., Levy, R. B., and Malek, T. R. Cutting Edge: Allogeneic CD4+ CD25+ Foxp3+ T regulatory cells suppress autoimmunity while establishing transplantation tolerance. J. Immunol. 176: 7149-7153, 2006.

Jin, H., Gong, D., Adeegbe, D., Bayer, A. L., Rolle, C., Yu, A. and Malek, T. R. Quantitative assessment concerning the contribution of IL-2Rβ for superantigen-mediated T cell responses in vivo. Int. Immunol. 18:565-572, 2006.

Bayer, A. L., Yu, A., Adeegbe, D. and Malek, T. R. Essential role for IL-2 for CD4+CD25+ T regulatory cell development during the neonatal period. J. Exp. Med. 201: 769-777, 2005.

Malek, T.R.. and Bayer, A.L. Tolerance, not immunity, crucially depends upon IL-2. Nature Rev. Immunol. 4:665-674, 2004.

Carrio, R., Bathe, O F., and Malek, T. R. Initial antigen encounter programs CD8+ T cells competent to develop into memory cells which is activated in an antigen-free, IL-7- and IL-15-rich environment. J. Immunol. 172: 7315-7323, 2004.

Jin, H., Carrio, R., Yu, A., and Malek, T. R. Distinct activation signals determined whether IL-21 induces B cell co-stimulation, growth arrest, or Bim-dependent apoptosis.  J. Immunol. 173: 657-665, 2004.

Malek, T.R. The main function of IL-2 is to promote the development of T regulatory cells. J. Leuk. Biol.  74: 961-965, 2003.

Yu. A, Zhou, J., Marten, N., Bergmann, C.C., Mammolenti, M., Levy, R. B., Malek, T. R. Efficient induction of primary and secondary T cell-dependent immune responses in vivo in the absence of functional IL-2 and IL-15 receptors. J. Immunol. 170:236-242, 2003.                                     

Bathe, O. F., Dalyot-Herman, N., and Malek, T. R. Emergence of antigen loss variants: therapeutic limitations in immunological targeting of a single antigen.  BMC Cancer 3: 21, 2003.

Malek, T. R. T helper cells, IL-2, and the generation of cytotoxic T cell responses. Trends Immunol. 23: 465-567, 2002.

Malek, T.R., Yu, A., Vincek, V., Scibelli, P., and Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2R b -deficient mice: Implications for the non-redundant function of IL-2. Immunity 17: 167-178, 2002.

Olosz, F. and Malek, T.R. Structural basis for binding multiple ligands by the common cytokine receptor g chain. J. Biol. Chem. 277:12047-12052, 2002.