During the last funding period, we made an unexpected discovery-that antigen-specific CD8+ T cells with the phenotype and function of memory cells were generated within days after dendritic cell (DC) immunization. This contrasts with infection, where substantially longer time periods are required for memory cell development. We extended this observation by showing that injection of CpG DMA, a TLR9 agonist that induces robust inflammation similar to infection, prevents accelerated generation of memory CD8+ T cells after DC immunization. This suggests the intriguing hypothesis that early inflammation controls the rate of memory cell generation. Secondly, we show that even very weak primary CD8+ T cell responses generated by DC vaccination can be rapidly amplified by booster immunizations given as early as 4-6 days after the initial immunization. The upshot of this finding is that booster immunization can elevate numbers of secondary effector and memory cells much faster after DC immunization than with vaccines that rely on live pathogens or immunization with inflammatory adjuvants. The ability of vaccines to rapidly generate large numbers of effector and memory CD8+ T cells against weak antigens may be critical under some conditions, specifically in tumor immunotherapy or in response to bioterrorism. In summary, the long-term goal of this competitive renewal application is to understand the factors that regulate the rate of memory T cell formation and how accelerated memory generation after DC vaccination can be used to enhance vaccine efficacy. This information is directly relevant to the design of vaccines that will generate the fastest and most robust protective immunity against infection or tumors. We will address this goal through the following specific aims:
Aim 1. Determine the timing, identity and cellular targets of the inflammatory signals that control the rate of memory CD8+ T cell generation.
Aim 2. Evaluate accelerated memory and prime-boost after DC immunization for CD4+ T cell responses, DC subsets and diverse antigen sources.
Aim 3. Determine if accelerated memory and prime-boost after DC immunization improves immunotherapy against established tumors and protection against malaria and leishmaniasis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046653-07
Application #
7179313
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Ferguson, Stacy E
Project Start
2006-02-15
Project End
2011-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
7
Fiscal Year
2007
Total Cost
$408,184
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Richer, Martin J; Nolz, Jeffrey C; Harty, John T (2013) Pathogen-specific inflammatory milieux tune the antigen sensitivity of CD8(+) T cells by enhancing T cell receptor signaling. Immunity 38:140-52
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
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
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
Pham, Nhat-Long L; Badovinac, Vladimir P; Harty, John T (2012) Epitope specificity of memory CD8+ T cells dictates vaccination-induced mortality in LCMV-infected perforin-deficient mice. Eur J Immunol 42:1488-99
Schmidt, Nathan W; Khanolkar, Aaruni; Hancox, Lisa et al. (2012) Perforin plays an unexpected role in regulating T-cell contraction during prolonged Listeria monocytogenes infection. Eur J Immunol 42:629-40
Pham, Nhat-Long L; Badovinac, Vladimir P; Harty, John T (2011) Differential role of ""Signal 3"" inflammatory cytokines in regulating CD8 T cell expansion and differentiation in vivo. Front Immunol 2:4
Kashiwada, Masaki; Pham, Nhat-Long L; Pewe, Lecia L et al. (2011) NFIL3/E4BP4 is a key transcription factor for CD8?? dendritic cell development. Blood 117:6193-7
Nolz, Jeffrey C; Harty, John T (2011) Protective capacity of memory CD8+ T cells is dictated by antigen exposure history and nature of the infection. Immunity 34:781-93
Butler, Noah S; Nolz, Jeffrey C; Harty, John T (2011) Immunologic considerations for generating memory CD8 T cells through vaccination. Cell Microbiol 13:925-33

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