The mechanisms controlling growth and differentiation of hematopoietic cells is not fully understood. Many of the inputs regulating these processes are governed by growth factors binding to the cell surface and activating tyrosine kinases. These studies investigate the role of Src kinases in mediating the differentiation of an unusual lineage of lymphocyte, termed NKT cells. Specifically, we recently demonstrated that mutants in the Src-related tyrosine kinase, Fyn, are severely compromised in the formation of NKT cells, but conventional lymphocyte development proceeds normally. NKT cells comprise a unique class of lymphocyte with characteristics of both natural killer (NK) cells and T lymphocytes. NKT cells are capable of suppressing deviant immune responses, including graft versus host disease and autoimmunity, and tumor metastasis. NKT cells express a limited T cell receptor (TCR) repertoire, with most utilizing the TCR Valpha14Jalpha281 alpha chain. The restricted TCR use may have evolved because NKT cells recognize, and are selected by the nonpolymorphic class I-like molecule CD1d. The long-term goal of this project is to understand the role of tyrosine kinases in regulating the development and function of NKT cells. The studies outlined here will focus on two main areas. The first part will be devoted to identifying some of the molecular features of Fyn which allow it to transduce signals involved in NKT cell development. Transgenic mice expressing different forms of Fyn or retroviruses encoding Fyn variants will be used to infect mutant bone marrow cells, then determining whether the modified cells develop into NKT cells. The second area will focus on identifying the other constituents of the Fyn dependent pathway necessary for NKT cell development. It is hypothesized that this pathway is required for rearrangement of the TCR alpha locus, and that ectopic expression of the Valpha14Jalpha281 alpha chain will stimulate NKT cell development in the fyn mutants. In addition, we will test the hypothesis that Fyn facilitates signaling from the GM-CSF receptor to promote NKT cell development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA086867-04
Application #
6878377
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Mufson, R Allan
Project Start
2004-05-10
Project End
2005-07-31
Budget Start
2004-05-10
Budget End
2005-07-31
Support Year
4
Fiscal Year
2003
Total Cost
$238,335
Indirect Cost
Name
Northwestern University at Chicago
Department
Dermatology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Ueda, Aki; Zhou, Liang; Stein, Paul L (2012) Fyn promotes Th17 differentiation by regulating the kinetics of ROR?t and Foxp3 expression. J Immunol 188:5247-56
Hix, Laura M; Shi, Yihui H; Brutkiewicz, Randy R et al. (2011) CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis. PLoS One 6:e20702
Kemp, Kyeorda L; Levin, Steven D; Stein, Paul L (2010) Lck regulates IL-10 expression in memory-like Th1 cells. Eur J Immunol 40:3210-9
Kemp, Kyeorda L; Levin, Steven D; Bryce, Paul J et al. (2010) Lck mediates Th2 differentiation through effects on T-bet and GATA-3. J Immunol 184:4178-84
Cen, Osman; Ueda, Aki; Guzman, Laura et al. (2009) The adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) regulates IFN-gamma and IL-4 production in V alpha 14 transgenic NKT cells via effects on GATA-3 and T-bet expression. J Immunol 182:1370-8
Rumble, Julie M; Oetjen, Karolyn A; Stein, Paul L et al. (2009) Phenotypic differences between mice deficient in XIAP and SAP, two factors targeted in X-linked lymphoproliferative syndrome (XLP). Cell Immunol 259:82-9