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.

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 (ZRG1-IMM-E (02))
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Lapham, Cheryl K
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University of Iowa
Schools of Medicine
Iowa City
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Doll, Katherine L; Pewe, Lecia L; Kurup, Samarchith P et al. (2016) Discriminating Protective from Nonprotective Plasmodium-Specific CD8+ T Cell Responses. J Immunol 196:4253-62
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