During the last funding period, we made the unexpected observation that memory CD8 T cells that developed after secondary stimulation exhibited a myriad of differences in phenotype and function from primary memory CD8 T cells(Jabbari and Harty, J. Exp. Med., 2006). More recently, we have observed that primary and secondary memory CD4 T cells also exhibit differences, however, with respect to one key molecule (CD62L, which controls homing of T cell to lymph nodes) primary and secondary memory CD4 T cells display the exact opposite pattern of expression to that seen on primary and secondary memory CD8 T cells. The fact that the immune system regulates access to lymph nodes differentially, not only between primary and secondary memory CD4 and CD8 populations, but also between CD4 and CD8 memory T cells, suggests important consequences to the overall function of the immune response. Additionally, although most current human vaccines employ booster immunizations and will thus generate secondary memory T cell populations, there are only a few studies besides ours on secondary memory CD8 T cells and essentially no published information on the characteristics of secondary CD4 T cell memory. Given the clear relevance of secondary memory to human vaccines that employ booster immunizations, we decided to focus (and re-title) this competitive renewal on "Regulation of primary and secondary CD4 and CD8 T cell memory" to address these knowledge gaps. This competitive renewal remains consistent with the long-term goals associated with the previous funding periods of this grant-to understand how memory T cells are generated and provide immunity to intracellular pathogens.
Aim 1. Define the characteristics of primary versus secondary memory CD4 T cells in response to infection.
Aim 2. Determine the mechanisms resulting in maintenance of secondary memory CD4 and CD8 T cells.
Aim 3. Evaluate functional differences between primary versus secondary memory CD4 T cells and CD8 T cells in response to pathogens with diverse characteristics.
Aim 4. Determine the molecular mechanisms that regulate the opposite patterns of CD62L expression in primary and secondary memory CD4 versus CD8 T cells.

Public Health Relevance

Booster immunizations are often used to enhance protective T cell numbers and are a common feature of vaccines used to protect humans against infectious disease. Our preliminary data generated during the last funding period shows that boosted (2? memory) T cells are quite different than 1? memory T cells. The goal of this proposal, to fully characterize the functional and molecular consequences imposed on T cell populations by multiple antigen exposures, 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
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI042767-14
Application #
8210918
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Lapham, Cheryl K
Project Start
1998-04-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$367,538
Indirect Cost
$122,513
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
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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