T cells play a central role in immunity to viruses but our knowledge of what is required at the cellular and molecular level to generate an anti-viral T cell response is not as extensive as it needs to be, particularly in light of the emergence of new strains of virus, and the potential of viruses to be use for bioterrorist activities. We propose to study several novel molecules in a superfamily, the TNF/TNFR family, that might be essential to the development of an anti-viral T cell response. These molecules might be targets for subverting the immune system away from protection either by the virus itself or in worse case scenario by bioterrorist manipulation. Conversely these molecules might be targets for improving our ability to effectively vaccinate. In all cases, without a basic understanding of their potential importance to the generation and persistence of anti-viral T cells, we are at a disadvantage. We hypothesize that the interactions of OX40/OX40L, HVEM- LIGHT, and 4-1BB-4-1BBL will play essential non-redundant roles in directing the priming of CD8 and CD4 cells induced by vaccinia virus and for inducing long-lasting memory. We will use both wt and recombinant vaccinia containing a defined CDS T cell epitope of ovalbumin in experiments with knockout animals for LIGHT, OX40, and 4-1BB to show their contributions to generating vaccinia-specific T cells. Additionally, we will use TCR transgenic CDS and CD4 T cells, reactive with OVA, and deficient in one of the above molecules, to specifically define the role on a T cell by tracking adoptively transferred T cells in vivo. These experiments will provide invaluable data on the importance of costimulatory members of the TNFR/TNF family in controlling T cell responses to vaccinia and highlight molecules that might be targets for future vaccination strategies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067341-02
Application #
7241591
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Challberg, Mark D
Project Start
2006-06-15
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$460,740
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Desai, Pritesh; Tahiliani, Vikas; Hutchinson, Tarun E et al. (2018) The TNF Superfamily Molecule LIGHT Promotes the Generation of Circulating and Lung-Resident Memory CD8 T Cells following an Acute Respiratory Virus Infection. J Immunol 200:2894-2904
Desai, Pritesh; Abboud, Georges; Stanfield, Jessica et al. (2017) HVEM Imprints Memory Potential on Effector CD8 T Cells Required for Protective Mucosal Immunity. J Immunol 199:2968-2975
Tahiliani, Vikas; Hutchinson, Tarun E; Abboud, Georges et al. (2017) OX40 Cooperates with ICOS To Amplify Follicular Th Cell Development and Germinal Center Reactions during Infection. J Immunol 198:218-228
Boettler, Tobias; Choi, Youn Soo; Salek-Ardakani, Shahram et al. (2013) Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1. J Immunol 191:5026-35
Flynn, Rachel; Hutchinson, Tarun; Murphy, Kenneth M et al. (2013) CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PLoS One 8:e77991
Gerlic, Motti; Faustin, Benjamin; Postigo, Antonio et al. (2013) Vaccinia virus F1L protein promotes virulence by inhibiting inflammasome activation. Proc Natl Acad Sci U S A 110:7808-13
Boettler, Tobias; Moeckel, Friedrich; Cheng, Yang et al. (2012) OX40 facilitates control of a persistent virus infection. PLoS Pathog 8:e1002913
Goulding, John; Bogue, Rebecka; Tahiliani, Vikas et al. (2012) CD8 T cells are essential for recovery from a respiratory vaccinia virus infection. J Immunol 189:2432-40
Zhao, Yuan; Croft, Michael (2012) Dispensable role for 4-1BB and 4-1BBL in development of vaccinia virus-specific CD8 T cells. Immunol Lett 141:220-6
Salek-Ardakani, Shahram; Moutaftsi, Magdalini; Sette, Alessandro et al. (2011) Targeting OX40 promotes lung-resident memory CD8 T cell populations that protect against respiratory poxvirus infection. J Virol 85:9051-9

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