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 #
5R37AI042767-12
Application #
7754430
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
2010-02-01
Budget End
2011-01-31
Support Year
12
Fiscal Year
2010
Total Cost
$371,250
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
Itani, Farah R; Sinha, Sushmita; Brate, Ashley A et al. (2017) Suppression of autoimmune demyelinating disease by preferential stimulation of CNS-specific CD8 T cells using Listeria-encoded neuroantigen. Sci Rep 7:1519
Gullicksrud, Jodi A; Li, Fengyin; Xing, Shaojun et al. (2017) Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection. J Immunol 199:911-919
Van Braeckel-Budimir, Natalija; Gras, Stephanie; Ladell, Kristin et al. (2017) A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. Immunity 47:835-847.e4
Sl├╝tter, Bram; Van Braeckel-Budimir, Natalija; Abboud, Georges et al. (2017) Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity. Sci Immunol 2:
Shan, Qiang; Zeng, Zhouhao; Xing, Shaojun et al. (2017) The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage. Nat Immunol 18:931-939
He, Bing; Xing, Shaojun; Chen, Changya et al. (2016) CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections. Immunity 45:1341-1354
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
Kim, Marie T; Kurup, Samarchith P; Starbeck-Miller, Gabriel R et al. (2016) Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals. J Immunol 197:1754-61
Kim, Marie T; Richer, Martin J; Gross, Brett P et al. (2015) Enhancing Dendritic Cell-based Immunotherapy with IL-2/Monoclonal Antibody Complexes for Control of Established Tumors. J Immunol 195:4537-44
Richer, Martin J; Pewe, Lecia L; Hancox, Lisa S et al. (2015) Inflammatory IL-15 is required for optimal memory T cell responses. J Clin Invest 125:3477-90

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