We have previously shown that bone marrow-derived professional antigen presenting cells (pAPC) are essential to prime CD8+ T cell responses against several viruses. However, the cell types and mechanisms whereby these anti-viral responses are primed are still unsolved. The current model, mostly inferred from experiments with non-infectious antigens (Ags), proposes that dendritic cells carry Ags from infected tissues to secondary lymphoid organs (SLO) where CD8+ T cells are primed. We think that this model is too simplistic and cannot account for the priming of all anti-viral CD8+ T cell responses. Furthermore, this model does not address whether the pAPC in the infected tissues must become infected with the virus and migrate thereafter to directly prime the responses, or whether it must avoid its own infection and acquire the viral Ags from other infected cells in order to maintain its migratory capacity. In this case cross-presentation could be the major mechanism involved in priming. Another possibility is that pAPC may not need to transport viral Ags to SLO but become infected or acquire the viral Ags when they are already in the SLO. In this scenario, uninfected pAPC in the tissues could sense infection, and rapidly migrate to SLO to wait for the arrival of the virus. Our hypothesis is that, in order to minimize immune evasion, Ag presentation is a flexible system that could use any of these mechanisms in order to adapt to the type of invading virus and the route of infection. In this project we will test this hypothesis using VACV and LCMV as our model viruses with the following specific Aims:
Specific Aim 1 : To determine and compare the ability of macrophages and DC to migrate to secondary lymphoid organs during viral infections.
Specific Aim 2 : To determine the ability of macrophages and DC to prime and cross-prime anti-viral naive CD8+ T cells in vivo.
Specific Aim 3 : To determine the role of bone marrow-derived pAPC in the activation of memory CD8+ T cells. These experiments should provide important information to understand the pathogenesis of viral infections and the induction of anti-viral CD8+ T cell responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048849-10
Application #
7991835
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2000-12-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
10
Fiscal Year
2011
Total Cost
$419,446
Indirect Cost
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Xu, Ren-Huan; Wong, Eric B; Rubio, Daniel et al. (2015) Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection. Immunity 43:1148-59
Fang, Min; Remakus, Sanda; Roscoe, Felicia et al. (2015) CD4+ T cell help is dispensable for protective CD8+ T cell memory against mousepox virus following vaccinia virus immunization. J Virol 89:776-83
Remakus, Sanda; Rubio, Daniel; Lev, Avital et al. (2013) Memory CD8⁺ T cells can outsource IFN-γ production but not cytolytic killing for antiviral protection. Cell Host Microbe 13:546-57
Remakus, Sanda; Sigal, Luis J (2013) Memory CD8⁺ T cell protection. Adv Exp Med Biol 785:77-86
Fang, Min; Siciliano, Nicholas A; Hersperger, Adam R et al. (2012) Perforin-dependent CD4+ T-cell cytotoxicity contributes to control a murine poxvirus infection. Proc Natl Acad Sci U S A 109:9983-8
Remakus, Sanda; Rubio, Daniel; Ma, Xueying et al. (2012) Memory CD8+ T cells specific for a single immunodominant or subdominant determinant induced by peptide-dendritic cell immunization protect from an acute lethal viral disease. J Virol 86:9748-59
Fang, Min; Orr, Mark T; Spee, Pieter et al. (2011) CD94 is essential for NK cell-mediated resistance to a lethal viral disease. Immunity 34:579-89
Remakus, Sanda; Sigal, Luis J (2011) Gamma interferon and perforin control the strength, but not the hierarchy, of immunodominance of an antiviral CD8+ T cell response. J Virol 85:12578-84
Xu, Ren-Huan; Remakus, Sanda; Ma, Xueying et al. (2010) Direct presentation is sufficient for an efficient anti-viral CD8+ T cell response. PLoS Pathog 6:e1000768
Ma, Xueying; Serna, Amparo; Xu, Ren-Huan et al. (2009) The amino acid sequences flanking an antigenic determinant can strongly affect MHC class I cross-presentation without altering direct presentation. J Immunol 182:4601-7

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