The development of memory T cells is essential to protection against many intracellular pathogens. Our studies have demonstrated that during an immune response to infection, a large portion of the effector and memory antigen-specific CD8 T cells are located in the non-lymphoid tissues. Memory cells residing in lymphoid and non-lymphoid tissues exhibit distinct functional and phenotypic characteristics. These subsets can be characterized as central memory T cells (Tcm, residing in lymphoid tissue) and effector memory T cells (Tem, found predominantly in non-lymphoid tissues). Our hypothesis proposes that na?ve T cell precursor frequency and antigen concentration and duration control memory lineage development. This proposal will focus on determining the role of these factors in driving memory lineage choice with respect to phenotype, function and location.
The specific aims are:
Aim 1. To determine whether antigen availability during primary and secondary responses to infection controls memory T cell development. Whether the duration of antigen availability and the timing of T cell entry into the response affect memory development will be tested using a novel system in which MHC-restricted antibody blockade will be used to inhibit CD4 and CD8 T cell responses following infection.
Aim 2. To determine the effects of endogenous naove CD8 T cell frequency and infection type on memory development. Our preliminary data indicated that endogenous naove CD8 T cells could be isolated and quantitated. Moreover, the naove CD8 T cell frequency and the infection type affected memory CD8 T cell development. Based on these data, the studies in this aim will test the hypothesis that endogenous naove CD8 T cell frequencies in conjunction with the duration of antigen availability control memory lineage choice.
Aim 3. To determine the effect of naove precursor frequency, infection type and antigen availability on in situ T cell activation . Our preliminary results identify formation of discrete clusters of antigen-specific CD8 T cells early during the primary immune response to infection. In addition, during reactivation, memory CD8 T cells migrate from the splenic marginal zones and in fact the B cell areas to the T cell zones in the white pulp. Using confocal microscopy and transgenic mice expressing a fluorescent reporter in dendritic cells we will determine the effect of endogenous naove precursor frequency, antigen duration and infection type on primary and secondary CD8 T cell responses in situ. In addition, we will visualize the location and reactivation characteristics of Tcm and Tem cells. These studies will provide a valuable link between anatomical characteristics of T cell activation and the functional development of memory T cells. Overall, these studies will provide important insight into the control of memory T cell lineage development in vivo in response to infection.Project narrative. This proposal is focused on understanding the generation of memory T cells in response to infection. Memory T cells are essential to provide protection against many infections so this research has substantial impact on understanding immunity and vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041576-14
Application #
7993538
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Rothermel, Annette L
Project Start
1997-08-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
14
Fiscal Year
2011
Total Cost
$362,637
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
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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