CD8 T cells are essential for clearance of intracellular pathogens. A current goal of vaccinology is to develop methods for inducing protective T cell mediated responses against some of the world's most intractable infectious diseases, including malaria and the human immunodeficiency virus. Effective vaccination requires the generation of long-lived memory cells with protective capabilities. Induction of a productive CD8 T cell response to robust infections represents a best case scenario but such models have yielded valuable insight into the regulation of memory CD8 T cell development. Thus far, vaccines geared toward promoting CD8 T cell immunity have generally not met with success. Therefore, identifying the checkpoints in memory CD8 T cell development along with the elements controlling those checkpoints continues to represent an important research goal. Our studies have focused on the detailed analysis of the factors that control the generation of central and effector memory CD8 T cells in response to bacterial and viral infections. Our results along with those from a number of other groups, have shown that activation of na?ve CD8 T cells in response to infection results in the generation of a heterogeneous population of effector cells with distinct phenotypic and functional properties. Our preliminary and published data supported by this long-standing grant, indicate that a population of early effector cells (EEC) are the sourc of the two major effector subsets: memory-precursor effector cells (MPEC), which generate memory cells, and short-lived effector cells (SLEC) which, at least in a primary response, are a terminal lineage. This proposal is aimed at exploring the central hypothesis that commitment to the memory lineage is designated at the EEC stage and further that EEC are themselves heterogeneous with respect to their developmental potential. This hypothesis will be examined in three specific aims:
Aim 1. To determine the developmental potential of EEC in response to the external milieu.
Aim 2. To identify the metabolic pathways in early effector cells leading to memory development.
Aim 3. To identify the molecular pathways that specify effector subset lineage development.

Public Health Relevance

CD8 T cells are required to protect against infectious pathogens. Vaccines aimed at promoting CD8 T cell mediated immunity are now being developed. The early events leading to the development of protective CD8 T cell memory are poorly understood and these studies will address that problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI041576-16A1
Application #
8580055
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Rothermel, Annette L
Project Start
1997-08-01
Project End
2017-07-31
Budget Start
2013-08-16
Budget End
2014-07-31
Support Year
16
Fiscal Year
2013
Total Cost
$380,280
Indirect Cost
$141,110
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
Sharma, Naveen; Benechet, Alexandre P; Lefrançois, Leo et al. (2015) CD8 T Cells Enter the Splenic T Cell Zones Independently of CCR7, but the Subsequent Expansion and Trafficking Patterns of Effector T Cells after Infection Are Dysregulated in the Absence of CCR7 Migratory Cues. J Immunol 195:5227-36
Bose, Tina O; Pham, Quynh-Mai; Jellison, Evan R et al. (2013) CD11a regulates effector CD8 T cell differentiation and central memory development in response to infection with Listeria monocytogenes. Infect Immun 81:1140-51
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
Turner, Damian L; Bickham, Kara L; Farber, Donna L et al. (2013) Splenic priming of virus-specific CD8 T cells following influenza virus infection. J Virol 87:4496-506
Sheridan, Brian S; Romagnoli, Pablo A; Pham, Quynh-Mai et al. (2013) γδ T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 39:184-95
Plumlee, Courtney R; Sheridan, Brian S; Cicek, Basak B et al. (2013) Environmental cues dictate the fate of individual CD8+ T cells responding to infection. Immunity 39:347-56
Sheridan, Brian S; Lefrançois, Leo (2012) Isolation of mouse lymphocytes from small intestine tissues. Curr Protoc Immunol Chapter 3:Unit3.19
Khanna, Kamal M; Lefrançois, Leo (2012) B cells, not just for antibody anymore. Immunity 36:315-7
Colpitts, Sara L; Stoklasek, Thomas A; Plumlee, Courtney R et al. (2012) Cutting edge: the role of IFN-α receptor and MyD88 signaling in induction of IL-15 expression in vivo. J Immunol 188:2483-7

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