Immunological memory is the basis for long-lasting protective immunity conferred by vaccination. The cells responsible for providing this protective immunity have different capabilities based on their location in the body, examples include sites exposed to the environment (i.e. lungs & intestine) or immune specific organs (i.e. lymph nodes). In order to construct better vaccines, we are trying to understand what drives the development of these different types of memory cells and how they might be related to one another. The memory T cell population is made up of at least two subsets of memory cells that have distinct homing and functional capacities. CD62L is important for the migration of lymphocytes through the high endothelial venules into lymphoid organs and is an effective marker in distinguishing 'central-memory' cells that reside in lymphoid organs and 'effector-memory' that reside largely in peripheral tissues. By having a diverse memory T cell population the host is provided with multiple layers of protection. How these subsets of memory cells are related to one another is an ongoing debate. We postulate that the two subsets are distinct cell lineages. In this proposal, we will examine whether epigenetic modifications occur within the memory precursor cells, which prevent the interconversion between these two subsets. We will examine whether during the immune response memory precursor cells that have lost CD62L expression have modified their chromatin in such a manner that precludes the re-expression of CD62L. We will also address how competition for resources/antigen affects this process. This proposal will allow us to gain a molecular understanding of memory cell differentiation through the use of chromatin immunoprecipitation assays, real-time RT-PCR and a CD62L reporter mouse system. By understanding how the responding CD8 T cells make their lineage decision we will be able to more effectively target a specific subset of memory cells which in turn may enable us to make more effective vaccines. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI074277-01A1
Application #
7331629
Study Section
Special Emphasis Panel (ZRG1-F07-L (20))
Program Officer
Prograis, Lawrence J
Project Start
2007-09-01
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$46,826
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Plumlee, Courtney R; Obar, Joshua J; Colpitts, Sara L et al. (2015) Early Effector CD8 T Cells Display Plasticity in Populating the Short-Lived Effector and Memory-Precursor Pools Following Bacterial or Viral Infection. Sci Rep 5:12264
Xu, Daqi; Fu, Han-Hsuan; Obar, Joshua J et al. (2013) A potential new pathway for PD-L1 costimulation of the CD8-T cell response to Listeria monocytogenes infection. PLoS One 8:e56539
Obar, Joshua J; Jellison, Evan R; Sheridan, Brian S et al. (2011) Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J Immunol 187:4967-78
Obar, Joshua J; Lefrancois, Leo (2010) Early events governing memory CD8+ T-cell differentiation. Int Immunol 22:619-25
Lefrancois, Leo; Obar, Joshua J (2010) Once a killer, always a killer: from cytotoxic T cell to memory cell. Immunol Rev 235:206-18
Obar, Joshua J; Lefrancois, Leo (2010) Memory CD8+ T cell differentiation. Ann N Y Acad Sci 1183:251-66
Obar, Joshua J; Lefrancois, Leo (2010) Early signals during CD8 T cell priming regulate the generation of central memory cells. J Immunol 185:263-72
Obar, Joshua J; Molloy, Michael J; Jellison, Evan R et al. (2010) CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses. Proc Natl Acad Sci U S A 107:193-8
Obar, Joshua J; Khanna, Kamal M; Lefrancois, Leo (2008) Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28:859-69