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.
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.
|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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