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. Lefrançois, 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.
 View more publications, see
Pubmed listing. |
