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Faculty Anthony T. Vella
Associate Professor of Immunology
Director, Graduate Program in Immunology
vella@uchc.edu
Areas of Interest:
My laboratory is focused in the area of T cell immunity.
Specifically, our goal is to uncover mechanisms used by T cells that
uncouple death pathways and permit these cells to survive for long
periods of time in vivo. Recently, we have found that T cell
costimulation provides an important growth signal, but does not confer
optimal T cell survival. Also, it has been shown that bacterial
lipopolysaccharide (LPS) prevents peripheral T cell deletion. In the
last 3 years we have combined these observations and found that these
stimuli synergize to promote profound T cell growth and survival. Based
on these data it has been suggested that a T cell benefit’s from having
three signals in vivo as opposed to two. This raises the question of
what is the nature of the third signal? To study these issues we have
developed three different T cell costimulation models.
In the first project we are examining the effects of CD40 ligation on
T cell immunity. Our data show that even though CD40 activation
significantly enhances T cell clonal expansion induced by superantigens
(SAg), they are still destined to die and do not permanently increase
the frequency of specific T cells. We found that the observed enhanced
clonal expansion was a function of CD28 ligation, also demonstrating
that ligation of CD28 does not block deletion in vivo. The question
raised was; could these T cells be protected from deletion? We found
that profound clonal expansion and long-term survival was substantially
enhanced when CD40 activation was combined with a small dose of
bacterial LPS. Our current studies are designed to uncover how synergism
is manifested in this model. Our approach is to analyze a role for
various cytokines including tumor necrosis facotor (TNF) by using TNF
receptor knockout animals and to begin to examine signaling molecules
via the same approach. In particular, we will examine NF-kB. Overall we
plan to find which pathway is important for T cell survival and then
work backwards to uncover which factors induced by LPS and CD40 promote
survival.
In the second project the goal is to understand how OX40 functions as
a T cell costimulatory signal. Just as with CD40, OX40 activation
enhances T cell clonal expansion but only moderately prevents deletion.
When OX40 ligation is combined with LPS stimulation, expansion and
rescue from deletion are substantially increased. This is particularly
intriguing because CD28 is the critical T cell costimulatory signal in
the CD40 model and OX40 is key in the other, and yet the results are the
same even though these molecules are in separate receptor families and
share little structural homology. This suggests that survival induction
may be funneled down the same intracellular signaling pathway.
Nevertheless, these results beg the question; can CD40 and OX40
stimulation synergize? The answer is no, only in the presence of LPS can
rescue be observed with activation of either, or both, of these
molecules. These data provide in vivo evidence for the existence of a
third signal that functions differently than costimulation. To uncover
how OX40 functions as a key growth signal for activated T cells, we have
performed and are performing a set of basic studies. Proliferative
capacity, cytokine production and cell surface phenotypes are beginning
to reveal several interesting features of this molecule. For instance,
we have shown that although there is an increase in clonal expansion the
rate of division has not changed. This was particularly confusing, but
later we found that OX40 did not enhance cell cycle entry, but it did
increase the number of rounds of division. In other words, we found that
Ag alone led to 3 or 4 cell cycles being completed, but OX40 ligation
promoted several more rounds of division. Our future goals are to
understand how OX40 ligation accomplishes this feat, which we will test
by carefully analyzing cytokine levels and signaling cascades.
Additionally, we are also interested in understanding how LPS synergizes
with OX40 ligation and whether this system is any different than the
CD28 model.
The third project is centered on understanding the nature of 4-1BB T
cell costimulation. 4-1BB, like OX40 and CD40, is a member of the TNF/NGF
superfamily of receptors. 4-1BB is expressed on both activated CD4 and
CD8 T cells. Using our SAg in vivo model we have investigated how ligation of this molecule will influence T cell activation in vivo. As
with the others, clonal expansion was increased, but in contrast, T cell
deletion was inhibited. Specifically, CD8 T cells were rescued, but not
CD4 T cells. This result was further accentuated by our recent findings
that Poly IC, in combination with 4-1BB ligation, dramatically enhanced
survival of both T cell subpopulations. As with the other models, we are
teasing apart which cytokines are involved and the responsive ability of
the rescued T cells. Perhaps, most interestingly, we have found that the
4-1BB stimulated T cells behave as regulatory cells in that they
profoundly inhibit T cell proliferation and cytokine production. We plan
to study how 4-1BB costimulation will influence anti-tumor responses
even though the co stimulated T cells appear to inhibit proliferation
and cytokine production. A major goal of this project is to understand
the nature of this suppressive effect and the mechanics of survival.
Publications
Selected Publications:
Lee, S.J., L. Myers, G. Muralimohan, J. Dai, Y. Qiao, Z. Li, R. S.
Mittler and A.T. Vella. 2004. 4-1BB and OX40 dual costimulation
synergistically stimulate primary specific CD8 T cells for robust
effector function. J. Immunol. 173: 3002-3012.
Yadav, R., D. J. Zammit, R. Salazar, L. Lefrancois, S. J. McSorley and
A.T. Vella. 2004. Dendritic Cell Activation as a Consequence of in vivo
stimulation with Superantigens versus PAMPs. Recent Research
Developments in Immunology. 6:31-43.
Rossi, R.J., G. Muralimohan, J.R. Maxwell and A.T. Vella. 2004.
Staphylococcal enterotoxins condition cells of the innate immune system
for Toll-like receptor 4 stimulation. International Immunology. 16:
1751-60.
Maxwell, J.R., R.J. Rossi, McSorley S.J. and A.T. Vella. 2004. T cell
clonal conditioning: A phase occurring early after Ag presentation but
prior to clonal expansion is impacted by Toll-like receptor stimulation.
J. Immunol. 2004 172: 248-259.
Myers, L, Takahashi C., Mittler R.S., R.J. Rossi and A.T. Vella.
2003. Effector CD8 T cells possess suppressor function after 4-1BB and
Toll-Like Receptor triggering. Proc Natl Acad Sci U S A . 100:5348-5353.
Byrd, C. M., T. C. Bolken, K. F. Jones, T.K.Warren, A. T. Vella, J.
Macdonald, D. King, J. Blackwood and D. E. Hruby. 2002. Biological
consequences of antigen and cytokine co-expression by recombinant
Streptococcus gordonii vaccine vectors. Vaccine. 20:2197-2205.
Maxwell, J.R., C. Ruby, N. I. Kerkvliet and A.T. Vella. 2002.
Contrasting the roles of costimulation and the natural adjuvant
lipopolysaccharide during the induction of T cell immunity. J. of Immunol. 168:4372-81.
Takahashi, C., R.S. Mittler and A.T. Vella. 2001. Contrasting the
effects of 4-1BB engagement between CD4 and CD8 activated T cell subsets
in vivo: Differential clonal expansion of CD4 and CD8 T cells to CD28
and 4-1BB ligation. Immunology Letters. 76(3):183-191.
Weatherill, A. R., Maxwell, J., A., Takahashi, C., Weinberg, A. D.
and A.T. Vella. 2001. OX40 ligation enhances cell cycle turnover of
Ag-activated CD4 T cells in vivo. Cell Immunol. 209(1):63-75.
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