: Typically, the CD4 T cell response to complex protein antigens is limited to one or a few peptide epitopes within that antigen, despite the fact that there are many potential peptides that can bind to the MHC molecules and elicit an immune response in the host. The experiments within this application seek to understand the elements in vivo that dictate this narrowed selection of specificity in CD4 T cells. Our current data suggest that the kinetic stability of peptide:MHC class II complexes is a major element that determines whether a particular peptide:class II complex will emerge as the dominant specificity in the developing CD4 T cell response. Our experiments are designed to comprehensively examine the impact of peptide:class II stability in the selection of peptides for CD4 T cell responses. We will determine the role that kinetic stability plays in DM editing within APC, in DM-mediated peptide association and dissociation in vitro and in the priming events in vivo mediated by dendritic cells. We will use a combination of molecular, biochemical and functional approaches to definitively and critically address this issue. We will evaluate peptides from independent and unrelated source antigens to determine degree of linkage between kinetic stability of peptide:MHC complexes, DM editing and immunodominance. Additionally, in order to extend our studies beyond correlative relationships, a major approach that will be used in the proposed experiments is to design peptide variants of selectively modulated kinetic stability that can be used in antigen presentation studies, biochemistry experiments and in immunization studies. The experiments within this application thus seek to demonstrate a causative relationship between the kinetic stability of peptide class II complexes with their immunological fate in the developing immune response. |

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051542-05
Application #
7112296
Study Section
Immunobiology Study Section (IMB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2002-09-30
Project End
2008-06-30
Budget Start
2006-09-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$346,048
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Richards, Katherine A; Nayak, Jennifer; Chaves, Francisco A et al. (2015) Seasonal Influenza Can Poise Hosts for CD4 T-Cell Immunity to H7N9 Avian Influenza. J Infect Dis 212:86-94
Alam, Shabnam; Knowlden, Zackery A G; Sangster, Mark Y et al. (2014) CD4 T cell help is limiting and selective during the primary B cell response to influenza virus infection. J Virol 88:314-24
Tung, Jacqueline; Sant, Andrea J (2013) Orchestration of CD4 T cell epitope preferences after multipeptide immunization. J Immunol 191:764-72
Sant, Andrea J; Chaves, Francisco A; Leddon, Scott A et al. (2013) The control of the specificity of CD4 T cell responses: thresholds, breakpoints, and ceilings. Front Immunol 4:340
Richards, Katherine A; Chaves, Francisco A; Alam, Shabnam et al. (2012) Trivalent inactivated influenza vaccines induce broad immunological reactivity to both internal virion components and influenza surface proteins. Vaccine 31:219-25
Leddon, Scott A; Sant, Andrea J (2012) The peptide specificity of the endogenous T follicular helper cell repertoire generated after protein immunization. PLoS One 7:e46952
Chaves, Francisco A; Lee, Alvin H; Nayak, Jennifer L et al. (2012) The utility and limitations of current Web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection. J Immunol 188:4235-48
Nayak, Jennifer L; Sant, Andrea J (2012) Loss in CD4 T-cell responses to multiple epitopes in influenza due to expression of one additional MHC class II molecule in the host. Immunology 136:425-36
Alam, Shabnam; Sant, Andrea J (2011) Infection with seasonal influenza virus elicits CD4 T cells specific for genetically conserved epitopes that can be rapidly mobilized for protective immunity to pandemic H1N1 influenza virus. J Virol 85:13310-21
Richards, Katherine A; Chaves, Francisco A; Sant, Andrea J (2011) The memory phase of the CD4 T-cell response to influenza virus infection maintains its diverse antigen specificity. Immunology 133:246-56

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