CD8+ T cells are important mediators of adaptive immunity to Listeria monocytogenes (LM) in wild-type (WT) BALB/c (H-2d MHC) and B6 (H-2b MHC) mice. In the last grant period, we determined that that perforin, IFN-gamma and TNF are not required CD8+ T cell effector molecules for resistance to LM infection. However, we also learned that perforin and IFN-gamma play key roles in regulating the normal expansion (perforin) and contraction (IFN-gamma) phases of antigen (Ag)-specific CD8+ T cell homeostasis after primary LM infection. Importantly, the absence of one or both molecules resulted in elevated levels of memory CD8+ T cells after vaccination, which may account for the observed protection. Thus, Aim 1 will determine if perforin and IFN-gamma are essential for optimal CD8+ T cell immunity to LM infection. We also demonstrated that vaccination of H-2b MHC TNF-deficient mice evoked high-level CD8+ T cell mediated antilisterial immunity. In H-2b mice, both MHC class Ia (classical) and MHC class Ib (non-classical) restricted CD8+ T cells participate in antilisterial immunity. Like IFN-gamma, TNF is a pleiotropic cytokine with the capacity to participate in the normal regulation of CD8+ T cell homeostasis. Consistent with this notion, we have evidence for altered homeostasis of MHC class Ia and class Ib restricted CD8+ T cells in TNF-deficient mice.
Aim 2 will determine how TNF regulates CD8+ T cell homeostasis and whether common mechanisms are used in regulation of MHC class Ia and MHC class Ib restricted CD8+ T cells. Recently, we showed that contraction of both primary and secondary CD8+ T cell responses was programmed, and independent of the rate of pathogen clearance or Ag-display. Importantly, these experiments showed that contraction of the secondary CD8+ T cell responses was markedly prolonged compared to contraction of the primary response, even in the same host animal. Since prolonged contraction of secondary responses may impact the function of memory cells in protective immunity, Aim 3 will address the mechanistic basis for this observation. Our long-term goal is to understand how memory CD8+ T cells are generated and provide immunity to intracellular pathogens. We will continue our analysis of the relationship between CD8+ T cell effector molecules, protective immunity and regulation of Ag-specific CD8+ T cell homeostasis through the following specific aims.
Aim -1. Determine the influence of perforin and/or IFN-gamma-deficiency on the protective capacity, repertoire and functional avidity of LM-specific memory CD8+ T cells.
Aim -2. Define the impact of TNF-deficiency on the homeostasis of Ag-specific CD8+ T cell responses to LM infection.
Aim -3. Investigate the mechanisms responsible for prolonged contraction of CD8+ T cells during the secondary response to infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042767-06
Application #
6785970
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Chiodetti, Lynda
Project Start
1998-04-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
6
Fiscal Year
2004
Total Cost
$295,000
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
Van Braeckel-Budimir, Natalija; Varga, Steven M; Badovinac, Vladimir P et al. (2018) Repeated Antigen Exposure Extends the Durability of Influenza-Specific Lung-Resident Memory CD8+ T Cells and Heterosubtypic Immunity. Cell Rep 24:3374-3382.e3
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
Osborn, Jossef F; Mooster, Jana L; Hobbs, Samuel J et al. (2017) Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8+ T cells. 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
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
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
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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