Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that sit at the boarder of adaptive and innate immunity. They have highly restricted T cell receptors (TCRs) that detect glycolipid antigen presented by the non-classical MHC molecule CD1d and they respond rapidly to antigen or cytokine stimulation. NKT cells play an important role in anti-microbial immune responses and because of their rapid production of multiple cytokines they are being considered as therapeutic agents in cancer and other diseases. NKT cells acquire their effector phenotype as a consequence of their unique mechanism of selection and differentiation in the thymus. The range of effector fates that NKT cells can acquire is only beginning to be appreciated but the mechanisms controlling NKT cell effector fate choice are completely unknown. Our research is directed at understanding the molecular mechanisms that control iNKT cell development with a focus on the E protein transcription factors, their inhibitors the ID proteins, and their downstream targets. These proteins are critical regulators of iNKT cell numbers and effector cell fate choice. In this grant application we propose experiments to determine the requirements for E2A in iNKT cell development an the consequences of over- and under-expression of two putative E2A target genes, Lef1 and Bcl6. Our studies will have a major impact on our understanding of how NKT cell number and function is regulated. In addition, our studies will provide insight into mechanisms to manipulate NKT cell effector fate and thereby alter immune responses at their inception.

Public Health Relevance

NKT cells have been implicated in multiple disease states with a failure of NKT cell function leading to autoimmune disease (e.g. Type 1 diabetes, Systemic Lupus Erythematosus, Rheumatoid Arthritis, Multiple Sclerosis) as well as susceptibility to cancer and tuberculosis. In contrast, inappropriate activation of NKT cells contributes to atherosclerosis, allergy, asthma and graft versus host disease. Our studies are directed at understanding the molecular mechanisms that control iNKT cell numbers and effector fate and will provide alternatives for interception of the immune response and thereby alter the course of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123396-02
Application #
9403219
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Prabhudas, Mercy R
Project Start
2016-12-19
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Verykokakis, Mihalis; Kee, Barbara L (2017) Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale. Eur J Immunol 47:454-457