Our long-term goal is to understand the molecular and cellular mechanisms for the generation of functional memory cytotoxic T lymphocytes (CTLs) for the purpose of developing more effective vaccines. Induction of protective memory CTLs is one of the major challenges in the development of effective vaccination against intracellular pathogens, such as HIV. However, the proteins required to generate functional memory CTLs are largely unknown. Biological function is based on proteins. We propose to identify the proteins involved in the regulation of memory CTL differentiation using high-throughput proteomics. We postulate that a limited number of proteins are responsible for memory differentiation, which can be identified by quantitative comparative proteomics. Our central hypothesis is that Key transcription factors related to survival are responsible for the regulation of memory CTL differentiation. We will utilize proteomic strategies to identify nuclear proteins that are potentially involved in the regulation of memory differentiation. In this R21 exploratory study, we will ask one major question: what are the most significant nuclear proteins whose abundances are altered when memory differentiation is regulated? First, we will seek to define the nuclear proteins differentially expressed during memory CTL differentiation during virus infection in animals. Second, through up regulation of memory CTLs through inhibition of mTOR by rapamycin, we will identify critical nuclear proteins whose abundances are further altered. To test our hypothesis, we will: 1) identify nuclear proteins potentially involved in memory CTL differentiation;2) identify nuclear proteins potentially involved in the enhancement of memory CTL by rapamycin;3) examine the transcription of potential targets identified in the first two aims. We expect that this work will lay the foundation for a future R01 application to study mechanisms for the generation of functional memory cytotoxic T lymphocytes, building on the leads revealed in this R21 work.

Public Health Relevance

The goal of our work is to elucidate the mechanisms by which the memory cytotoxic T cell immune response is developed. In this proposal we present a plan to identify critical nuclear proteins involved in the regulation of the immune response. Such knowledge will provide a foundation for the development of effective vaccines against HIV and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI095715-01A1
Application #
8299729
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
2012-02-01
Project End
2014-01-28
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$228,000
Indirect Cost
$78,000
Name
University of Maryland College Park
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Garcia, K; Sun, Z; Mattson, E et al. (2014) IL-12 is required for mTOR regulation of memory CTLs during viral infection. Genes Immun 15:413-23
Mattson, Elliot; Xu, Lingyang; Li, Lei et al. (2014) Transcriptome profiling of CTLs regulated by rapamycin using RNA-Seq. Immunogenetics 66:625-33
Smyth, Kendra; Garcia, Karla; Sun, Zhifeng et al. (2013) TLR agonists are highly effective at eliciting functional memory CTLs of effector memory phenotype in peptide immunization. Int Immunopharmacol 15:67-72
Sun, Zhifeng; Smyth, Kendra; Garcia, Karla et al. (2013) Nicotine inhibits memory CTL programming. PLoS One 8:e68183
Sun, Zhifeng; Xiao, Zhengguo (2013) 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) regulates CTL activation and memory programming. Biochem Biophys Res Commun 435:472-6
Xiao, Zhengguo; Sun, Zhifeng; Smyth, Kendra et al. (2013) Wnt signaling inhibits CTL memory programming. Mol Immunol 56:423-33