Conventional and non-conventional T cells develop in the thymus. Non-conventional T cells that have features typically associated with innate immune cells are termed innate-like lymphocytes (ILLs). We and others have described a population of CD8+ ILLs, characterized by expression of the activation/memory markers CD44 and CD122, expression of the T-box transcription factor Eomesodermin (Eomes) and ability to produce IFN? rapidly after ex vivo stimulation. These CD8+ ILLs develop via a cell-extrinsic mechanism mediated by IL-4 production from a population of thymocytes that express promyelocytic leukemia zinc finger protein (PLZF), a known transcriptional regulator of innate cells. This proposal describes a 5-year career development plan and research strategy to develop an independent career as a laboratory-based academic physician scientist. Under the mentorship of Dr. Gary Koretzky, and utilizing the outstanding training environment in the Division of Hematology/Oncology at the University of Pennsylvania, this plan will help the candidate foster the skills needed for her to become an independent investigator evaluating the role of ILLs in the immune responses. The proposed research strategy aims to investigate the novel mechanism of cytokine driven T cell development and to define the function of CD8+ ILLs. Employing complementary in vitro and in vivo strategies, the focus of Aim 1 is to elucidate how Eomes and the IL-4 signaling pathway regulate CD8+ ILL development. There is currently scant data regarding the function of CD8+ ILLs. Therefore, Aim 2 is designed to investigate the role of CD8+ ILLs in response to bacterial and viral pathogens.

Public Health Relevance

When the immune system fails to adequately protect the host from infections and tumors, medical therapies (i.e., vaccines or immunotherapy) may help to improve immune function. This proposal describes a strategy to characterize the development and function of a newly described population of immune cells, called CD8+ innate-like lymphocytes (CD8+ ILLs). Understanding of the role of CD8+ ILLs in immune responses to infection may lead to the potential for future therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AI101008-01
Application #
8354211
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Prograis, Lawrence J
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$133,758
Indirect Cost
$9,908
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Fraietta, Joseph A; Nobles, Christopher L; Sammons, Morgan A et al. (2018) Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558:307-312
Carty, Shannon A; Gohil, Mercy; Banks, Lauren B et al. (2018) The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation. J Immunol 200:82-91
Prince, Amanda L; Kraus, Zachary; Carty, Shannon A et al. (2014) Development of innate CD4+ and CD8+ T cells in Itk-deficient mice is regulated by distinct pathways. J Immunol 193:688-99
Carty, Shannon A; Koretzky, Gary A; Jordan, Martha S (2014) Interleukin-4 regulates eomesodermin in CD8+ T cell development and differentiation. PLoS One 9:e106659