Our goal is to define how pro-inflammatory cytokines and factors derived from toll-like receptor (TLR) stimulation impact specific CD4 T cell immunity in vivo. Characterizing this process will improve adjuvant development by defining new methods to control in vivo T cell responses while minimizing toxicity. This goal is based on our recent work which unveiled an unexpected division of labor between the TLR4 adaptors. One path signaled T cell effector differentiation and homing to solid organs, and the other path was responsible for clonal expansion and inducing cell survival. Therefore, uncovering how the adjuvant response emanating from the TLR4 pathway affects T cell behavior will allow vaccinologists to push desirable effects on Ag-specific CD4 T cells. This goal will be accomplished in 3 specific aims by determining the mechanism of how each adaptor impacts T cells.
In Aim 1 we will determine how TRIF controls T cell effector differentiation and homing by examining an innate cytokine axis that we hypothesize potentiates both cell behaviors. Data from this aim will help design vaccine formulations that will aid in driving effector T cell migration to specific sites of the body.
In Aim 2 a proteomic map of specific CD4 T cells destined to survive will be captured and contrasted to the same specific T cells programmed to die. We will accomplish this goal using an innovative liquid fractionation approach that will permit us to mine the proteome for differential changes between these populations.
Aim 3 will capitalize on our novel finding demonstrating that Ag-experienced CD4 T cells can facilitate adjuvant toxicity. We will define this process and develop new approaches to counter toxicity while promoting strong adjuvant responses. Thus, the results from this proposal will provide an "adjuvant to toxicity" ratio that can be used to gauge the effectiveness and safety of TLR agonists, and importantly provide an evidence-based approach to designing adjuvant therapeutics.

Public Health Relevance

CD4 T cells play a crucial in the immune response against pathogens, tumors and environmental factors. They interact with the innate immune system to modulate immune responses and our studies will examine new ways to modify T cell responses in a beneficial manner for biomedical therapy. Our goal is to uncover ways that innate and adaptive immune cells can be induced to fortify vaccines while minimizing toxicity and how they can be used to control infectious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI042858-12A1
Application #
8237104
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Leitner, Wolfgang W
Project Start
1999-07-01
Project End
2017-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$382,756
Indirect Cost
$132,756
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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McAleer, Jeremy P; Vella, Anthony T (2010) Educating CD4 T cells with vaccine adjuvants: lessons from lipopolysaccharide. Trends Immunol 31:429-35
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Menoret, Antoine; McAleer, Jeremy P; Ngoi, Soo-Mun et al. (2009) The oxazolidinone derivative locostatin induces cytokine appeasement. J Immunol 183:7489-96
Ngoi, Soo M; Tovey, Michael G; Vella, Anthony T (2008) Targeting poly(I:C) to the TLR3-independent pathway boosts effector CD8 T cell differentiation through IFN-alpha/beta. J Immunol 181:7670-80
Muralimohan, Guruprasaadh; Rossi, Robert J; Guernsey, Linda A et al. (2008) Inhalation of Staphylococcus aureus enterotoxin A induces IFN-gamma and CD8 T cell-dependent airway and interstitial lung pathology in mice. J Immunol 181:3698-705

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