My research program at the University of Maryland centers on understanding
the molecular events in T cell activation and tolerance. The two main
areas of study are (1) Signaling events in T cell anergy; and
(2) Regulation of metabolism during T cell activation.
(For those of you who don't remember your immunology, click here for a little review.)
Signaling Events in T Cell Anergy
The tremendous diversity of T cell antigen receptors presents a
double-edged sword, with flexibility and the ability to rapidly respond to
novel stimuli coming at the cost of potential autoimmunity. In order to
minimize the risk of autoimmunity, T cell undergo a process of
"education" in the thymus, during which the majority of T cells
recognizing self-antigens undergo programmed cell death. Although thymic
deletion goes a long way toward eliminating autoreactive T cells, it is
not a perfect system, and significant numbers of autoreactive T cells
escapethe thymus and can be detected in the bloodstream, even in healthy
people. These cells must be kept in check in the periphery, via a
processes collectively known as peripheral tolerance. Multiple mechanisms
can lead to tolerance in peripheral T cells, and the focus of this project
is on how the cell-autonomous regulation of autoreactive T cells is
achieved through the induction of anergy.
Anergy is a state of hyporesponsiveness resulting from activation under
non-inflammatory conditions, and in T cells, this is characterized by a
failure to proliferate or produce interleukin-2 (IL-2) upon subsequent
restimulation. This presents a puzzle: Why does the immune system keep
cells that have been determined to be potentially dangerous, and which
appear to have been rendered non-functional? The retention of anergic
cells suggests that they may serve purposes other than "helper" or
"killer". In addition, the presence of anergic T cells may provide a pool
of T cells that can be recruited for therapeutic purposes, such as in
cancer immunotherapy. My laboratory is interested in understanding the
capabilities and limitations of anergic cells. We study this using a
transgenic mouse system, in which anergy can be induced by a variety of
methods, both in vivo and in vitro, and are examining the roles of
different signal transduction pathways (including the PI3K, Fyn, cAMP, and
Ca++ signaling pathways) in both the induction and maintenance of the
hyporesponsive state.
Regulation of Metabolism During T Cell Activation