| dc.description.abstract |
<p>Throughout their development in the thymus and during their maintenance and the
immunological response in the periphery, T cells rely on the regulation of classical
apoptotic pathways to promote cell survival or death. Several proteins of the Bcl-2
family have been shown to be critical in thymocyte and T cell survival and consequently,
in T cell function. Among these proteins, the antiapoptotic proteins Bcl-2 and Mcl-1
are critical for promoting T cell survival at multiple stages of the T cell "life
cycle." While these proteins have been reported to interact with several of the proapoptotic
members of the Bcl-2 family, the specific interactions by which Mcl-1 in particular
promotes T cell survival in vivo were not well understood. Further, how different
stimuli (for example, cytokine signaling and T cell activation) modulate the specific
functions of Mcl-1 had also not been thoroughly explored. </p><p>We utilized mouse
models to dissect the roles of Mcl-1 at multiple stages of T cell development and
function. We utilized conditional knockout and double knockout strategies to build
genetic pathways for Mcl-1 activity during thymocyte development and in peripheral
T cells under a variety of conditions. In the thymus, the major role of Mcl-1 is to
inhibit the activity of proapoptotic Bak because the loss of Bak, but not the loss
of Bax or Bim, rescued the survival of Mcl-1-deficient thymocytes at both the double
negative and single positive stages. Further, we concluded that this role is not shared
with Bcl-2 because overexpression of Bcl-2 did not rescue DN or SP survival. </p><p>In
peripheral T cells, the loss of Bak rescued T cell survival in the presence of IL
7, but not during conditions of cytokine withdrawal. Interestingly, the overexpression
of Bcl-2 or the loss of Bim partially rescued the survival of T cells during cytokine
withdrawal, indicating that Mcl-1 has dual roles in T cells: cytokine-dependent and
cytokine independent. Additionally, we found that cytokines of the common gamma chain
family have different effects on the activity of Mcl-1 due to the differential regulation
of other proteins of the Bcl-2 family, most notably Bim.</p><p>Finally, we utilized
a Bcl-2 reporter mouse model to examine the role of Bcl-2 in the establishment of
CD8+ T cell memory to infection. Although it is known that Bcl-2 is dynamically regulated
in response to activation, the importance of this regulation in the establishment
of T cell memory is not yet clear. We show that a subset of effector T cells within
a previously defined memory precursor population retained high Bcl-2 expression at
the peak of the immune response. Using adoptive transfer of sorted effector T cells,
we provide preliminary evidence that the cells with memory potential lie within a
strict range of Bcl-2 expression. These studies indicate that the regulation of Bcl
2 is likely critical in establishing T cell memory and provide a platform for the
future study of the factors that influence T cell memory.</p>
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