This proposal is aimed at understanding the development, rapid function, and localization of CD8+ T cells that respond in the absence of cognate antigen during bacterial infections, with the hypothesis that CD8+ T cells are important contributors to the early, innate production of IFN-gamma.
The specific aims are: I: To analyze the survival, localization and protective ability of memory CD8+ T cells vs. NK cells during a Listeria monocytogenes (LM) infection. In this aim we will dissect the differences in protective ability between NK and memory CD8+ T cells responding to LM in a non-antigen specific fashion. We will use immunocytochemistry to analyze the location of the responding populations of transferred cells within the organs targeted by LM infection. In addition, the ability of memory CD8+ T and NK cells to survive after responding to LM will be measured using immunocytochemistry and flow cytometry. II: To determine the role of CD8+ T cells in aiding in the polarization of CD4+ T cells. Our data shows that memory CD8+ T cells rapidly secrete IFN-gamma independent of cognate antigen and thus play an important role in the innate immune response, which is essential in promoting TH1 development through the secretion of cytokines. We will now directly test the ability of CD8+ T cells and NK cells to influence TH1 development by secreting IFN-gamma using co-transfer protocols to analyze the polarization of CD4+ T cells in response to pathogens. III: To analyze the effects of IL-12 and IL-18 on naive and effector/memory CD8+ T cells. In the first part of this aim, we will determine which cytokines, if any, are required in order to establish IL-12/IL-18 responsiveness during the transition of naive CD8+ T cells into primed, effector cells. In the second part of the aim, we will determine the functional outcomes of signaling through the IL-12 and IL-18 receptors and compare that with signaling through the TCR using microarray analysis and real-time RT-PCR. These studies will further our understanding of innate immune responses to pathogens mediated by CD8+ T cells and allow us to better combat infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI064592-02
Application #
7078547
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Prograis, Lawrence J
Project Start
2005-07-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$108,000
Indirect Cost
Name
University of North Texas
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Carr, Karen D; Sieve, Amy N; Indramohan, Mohanalaxmi et al. (2011) Specific depletion reveals a novel role for neutrophil-mediated protection in the liver during Listeria monocytogenes infection. Eur J Immunol 41:2666-76
Graham, Amy C; Carr, Karen D; Sieve, Amy N et al. (2011) IL-22 production is regulated by IL-23 during Listeria monocytogenes infection but is not required for bacterial clearance or tissue protection. PLoS One 6:e17171
Sieve, Amy N; Meeks, Karen D; Lee, Suheung et al. (2010) A novel immunoregulatory function for IL-23: Inhibition of IL-12-dependent IFN-ýý production. Eur J Immunol 40:2236-47
Meeks, Karen D; Sieve, Amy N; Kolls, Jay K et al. (2009) IL-23 is required for protection against systemic infection with Listeria monocytogenes. J Immunol 183:8026-34
Sieve, Amy N; Meeks, Karen D; Bodhankar, Sheetal et al. (2009) A novel IL-17-dependent mechanism of cross protection: respiratory infection with mycoplasma protects against a secondary listeria infection. Eur J Immunol 39:426-38
Berg, Rance E; Forman, James (2006) The role of CD8 T cells in innate immunity and in antigen non-specific protection. Curr Opin Immunol 18:338-43
Berg, Rance E; Crossley, Emily; Murray, Sean et al. (2005) Relative contributions of NK and CD8 T cells to IFN-gamma mediated innate immune protection against Listeria monocytogenes. J Immunol 175:1751-7