Thomas R. Malek, Ph.D.
Professor of Microbiology & Immunology
Description of Research
Treg cells are essential to suppress autoreactive T cells that escape thymic negative selection. Without Treg cells, severe autoimmunity occurs. In the absence of IL-2 receptor (IL-2R) signaling, T regulatory cell development fails, leading to rapid lethal autoimmunity. In the periphery, IL-2 also provides essential signals for mature Treg cell homeostasis and function. Dr. Malek’s laboratory is investigating the basis by which IL-2 controls thymic development. They are also defining those activities by mature Treg cells that depend upon IL-2. Using novel mouse models that express mutant IL-2Rs that deliver distinctive signals, they are particularly interested in defining those IL-2-dependent activities that require differential IL-2R signals. Dr. Malek and his colleagues hypothesize that those activities which require the most stringent IL-2R signaling represent a risk for autoimmune disease and may be related to the genetic predisposition for type-1 diabetes, multiple sclerosis, and rheumatoid arthritis in humans mapping to the IL-2 and IL-2R genes. They are also evaluating the mechanism by which IL-2 boosts Treg numbers and protects mice from autoimmunity. Another related area of work is to define the requirements for Treg TCR diversity and specificity in control of autoimmunity.
Long lasting protective immunity requires effective primary responses and the development of memory. IL-2 also provides essential signals for immune responses by promoting terminal differentiation of effector cells with enhanced function and T cell memory production. Dr. Malek is studying the extent IL-2R signaling programs T cell memory development versus simply promoting memory T cell survival. As IL-2 and IL-15 utilize identical receptor signaling subunits, he also determines how signaling by these two cytokine mediate unique biological responses. His laboratory is applying their understanding of IL-2 in pre-clinical models to examine whether IL-2 boosts the activity of tumor vaccines that elicit cell-mediated immunity and enhances memory production. This latter point is related to improving the efficacy of vaccines to infectious agents as well as tumors.
- IL-2 is essential for Treg production
- IL-2 is functional at multiple levels for Treg cells, for thymic development, for rapid expansion in neonatal lymph nodes, and for homeostasis in mature peripheral immune tissues
- A low IL-2R signaling threshold is sufficient for Treg development and homeostasis
- Treg cells with limited TCR diversity suppress autoimmunity
- Protective tumor immunity is predicted by the development of T cell memory
- The IL-7R provides a unique non-redundant signal in promoting CD8+ T memory cell survival
Selected Cancer-Related Publications
- Bayer AL, Jones M, Chirinos J, de Armas L, Schreiber TH, Malek TR, Levy RB. Host CD4+CD25+ T cells can expand and comprise a major component of the Treg compartment after experimental HCT. Blood 113:733-43, 2009. Read more »
- Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30:204-17, 2009. Read more »