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.
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|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|
|Slütter, 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:|
|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|
|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|
|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|
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