of research plan for MERIT extension. Memory T cell populations with a history of repeated antigen exposure will be generated in humans due to recurring infections (ie, malaria, influenza), chronic and latent infections (CMV, EBV), and cancer. In addition, many vaccines rely on multiple immunizations (prime-boost) to generate adequate levels of immunity to prevent infection. Our long-term goal is to understand the impact of antigen-exposure history on the properties ofthe resulting memory T cell populations. The significance of these studies lies in providing the basic information necessary to rationally design next generation vaccines with the capacity to protect against diseases of global import such as malaria, HIV and TB that have proven intractable to current vaccine efforts and to lay the groundwork for protective vaccines against emerging and pandemic diseases. Our published and unpublished results from the initial ~3.5 year funding period of R37AI42767 reveal that repeated antigen exposure profoundly impacts patterns of gene expression in the resulting memory CD8 T cell compartment. Functional studies carried out in concert reveal that repeated antigen exposure also alters T cell localization in the steady state and negatively impacts memory maintenance and proliferative capacity in response to antigen re-encounter. Importantly, we also showed that, depending on the nature ofthe pathogen, repeated antigen exposure can either increase or decrease the per cell protective capacity of memory CDS T cells. Despite this progress, many important questions remain to be answered before we can develop ways to utilize repeated antigen-exposure to shape vaccine induced T cell responses for effective protection against specific pathogens. Thus, we retain the long-term goals from our initial funding period for this proposed MERIT extension. Based on the information we generated during the initial funding period and as highlighted in the "implications for future studies" sections in the progress report, we will focus our efforts in the MERIT extension period on three specific areas 1. Dissecting the molecular basis for diminished persistence of memory CDS T cells generated by repeated antigen stimulation. 2. Understanding how the changes in chemokines, chemokine receptors and adhesion molecules induced by repeated antigen-stimulation influence the steady state and inflammatory based trafficking patterns of the resulting memory populations and how these changes influence pathogen-specific protective immunity. 3. Determining how multiple antigen-encounters regulate the T cell intrinsic and T cell extrinsic (ie, access to specific APC) defects in proliferative response to reinfection. Completion of these studies will not only provide novel information regarding the impact of antigenexposure history on memory T cell but also lay the groundwork for using this information to improve vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
Program Officer
Kelly, Halonna R
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University of Iowa
Schools of Medicine
Iowa City
United States
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Nolz, Jeffrey C; Harty, John T (2014) IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking. J Clin Invest 124:1013-26
Gorman, Jacob V; Starbeck-Miller, Gabriel; Pham, Nhat-Long L et al. (2014) Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J Immunol 192:3133-42
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
Khanolkar, Aaruni; Williams, Matthew A; Harty, John T (2013) Antigen experience shapes phenotype and function of memory Th1 cells. PLoS One 8:e65234
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
Slutter, Bram; Pewe, Lecia L; Lauer, Peter et al. (2013) Cutting edge: rapid boosting of cross-reactive memory CD8 T cells broadens the protective capacity of the Flumist vaccine. J Immunol 190:3854-8
Slutter, Bram; Pewe, Lecia L; Kaech, Susan M et al. (2013) Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus. Immunity 39:939-48
Butler, Noah S; Moebius, Jacqueline; Pewe, Lecia L et al. (2012) Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol 13:188-95
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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