Natural killer (NK) T cells are a subset of lymphocytes that play an important role in the response to M. tuberculosis and in preventing autoimmune disease and cancer but their inappropriate activation can lead to diseases such as atherosclerosis, allergy or asthma. NKT cells recognize glycolipid antigen presented on CD1d through their T cell receptor but they also express activating receptors commonly associated with NK cells, and they exist in an primed state allowing them to produce copious amounts of cytokine rapidly after encounter with antigen. NKT cells acquire this effector phenotype as a consequence of their unique mechanism of selection and differentiation in the thymus. However, the range of effector fates that NKT cells can acquire is only beginning to be appreciated and the mechanisms controlling NKT cell effector fate choice is completely unknown. My research is directed at understanding the molecular mechanisms that control development of adaptive and innate lymphocytes with a focus on the E protein basic helix-loop-helix (bHLH) transcription factors and their antagonists the Id proteins. These proteins are critical regulators of lymphocyte development and in the NKT cell lineage we hypothesize that these bHLH proteins control both positive selection of NKT cells and their choice of effector cell fate. In this grant application w propose to determine: 1) the range of NKT cell effector fates controlled by bHLH proteins and 2) the role of E protein dose in selection of the E protein target genes that drive these effector fat choices. Our studies will have a major impact on our understanding of how NKT cells function and how their development and effector states are controlled. 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. Understanding the range of effector fates that an NKT cell can acquire is critical to understanding how these cells impact the immune response. Moreover, determining the mechanisms controlling these effector fates 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
High Priority, Short Term Project Award (R56)
Project #
1R56AI104303-01A1
Application #
8735243
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
2013-09-24
Project End
2014-08-31
Budget Start
2013-09-24
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$366,066
Indirect Cost
$131,066
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Verykokakis, Mihalis; Zook, Erin C; Kee, Barbara L (2014) ID'ing innate and innate-like lymphoid cells. Immunol Rev 261:177-97
Verykokakis, Mihalis; Krishnamoorthy, Veena; Iavarone, Antonio et al. (2013) Essential functions for ID proteins at multiple checkpoints in invariant NKT cell development. J Immunol 191:5973-83