The ability to develop and sustain populations of memory CD8 T cells after infection or immunization is a hallmark of the adaptive immune response and one basis for protective vaccination against infectious disease or in cancer immunotherapy. Since the level of protection to infection is proportional to the number of memory CD8 T cells present at the time of pathogen exposure, many vaccines in use today involve an initial immunization that is followed by one or more booster ('prime-boost'protocols) immunizations. Similarly, individuals that receive only a single immunization may receive a secondary stimulation when they encounter the pathogen and, even in the absence of vaccination individuals might be exposed to multiple rounds of infection with the same pathogen. Therefore, there is a need to understand CD8 T cell responses generated after numerous antigen exposures. Importantly, most studies of memory CD8 T cells have focused on the response to primary (1o) infection or vaccination. This is a critical knowledge gap since it is not known how the number of Ag-exposures can influence the characteristics of CD8 T cell populations and their ability to defend against infection. Our long term goal is to fully understand the functional consequences imposed on CD8 T cell populations by multiple antigen encounters. This information will be significant in understanding how best to generate and manipulate protective immunity achieved by vaccination. We will test the central hypothesis that the number of antigen-stimulations will dictate the important phenotypic and functional characteristics of memory CD8 T cell populations. We are well prepared to undertake these studies based upon our expertise in mouse models of infections and CD8 T cell immunity coupled with the guidance of strong preliminary data. We have developed novel methodologies that will enable comprehensive and detailed analyses of CD8 T cell populations responding to multiple antigen encounters. Thus, we propose the following Specific Aims: SA1 - Determine how the number of antigen encounters controls the longevity of CD8 T cells. SA2 - Evaluate the phenotypic and functional differences between memory CD8 T cell populations in response to multiple antigen-stimulations. SA3 - Define the role of inflammation in generation of secondary (2o) and tertiary (3o) memory CD8 T cell responses. Public Health Relevance: Most studies of memory CD8 T cells have focused on the response to primary (1o) infection and/or vaccination. However, booster immunizations are often used to increase protective CD8 T cell numbers and are common feature of vaccines used to protect humans against infectious disease. The goal of this proposal, to fully characterize the functional consequences imposed on CD8 T cell populations by multiple rounds of Ag-stimulations, will be significant in understanding how best to generate protective immunity by vaccination.

Public Health Relevance

Most studies of memory CD8 T cells have focused on the response to primary (1o) infection and/or vaccination. However, booster immunizations are often used to increase protective CD8 T cell numbers and are common feature of vaccines used to protect humans against infectious disease. The goal of this proposal, to fully characterize the functional consequences imposed on CD8 T cell populations by multiple rounds of Ag-stimulations, will be significant in understanding how best to generate protective immunity by vaccination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083286-04
Application #
8286365
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Lapham, Cheryl K
Project Start
2009-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$364,325
Indirect Cost
$119,300
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Cabrera-Perez, Javier; Condotta, Stephanie A; Badovinac, Vladimir P et al. (2014) Impact of sepsis on CD4 T cell immunity. J Leukoc Biol 96:767-77
Duong, Sean; Condotta, Stephanie A; Rai, Deepa et al. (2014) Polymicrobial sepsis alters antigen-dependent and -independent memory CD8 T cell functions. J Immunol 192:3618-25
Rai, Deepa; Martin, Matthew D; Badovinac, Vladimir P (2014) The longevity of memory CD8 T cell responses after repetitive antigen stimulations. J Immunol 192:5652-9
Starbeck-Miller, Gabriel R; Badovinac, Vladimir P; Barber, Daniel L et al. (2014) Cutting edge: Expression of Fc?RIIB tempers memory CD8 T cell function in vivo. J Immunol 192:35-9
Condotta, Stephanie A; Rai, Deepa; James, Britnie R et al. (2013) Sustained and incomplete recovery of naive CD8+ T cell precursors after sepsis contributes to impaired CD8+ T cell responses to infection. J Immunol 190:1991-2000
Condotta, Stephanie A; Cabrera-Perez, Javier; Badovinac, Vladimir P et al. (2013) T-cell-mediated immunity and the role of TRAIL in sepsis-induced immunosuppression. Crit Rev Immunol 33:23-40
Martin, Matthew D; Condotta, Stephanie A; Harty, John T et al. (2012) Population dynamics of naive and memory CD8 T cell responses after antigen stimulations in vivo. J Immunol 188:1255-65
Condotta, Stephanie A; Richer, Martin J; Badovinac, Vladimir P et al. (2012) Probing CD8 T cell responses with Listeria monocytogenes infection. Adv Immunol 113:51-80
Nolz, Jeffrey C; Rai, Deepa; Badovinac, Vladimir P et al. (2012) Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells. Proc Natl Acad Sci U S A 109:6199-204
Martin, Matthew D; Wirth, Thomas C; Lauer, Peter et al. (2011) The impact of pre-existing memory on differentiation of newly recruited naive CD8 T cells. J Immunol 187:2923-31

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