Cell-surface proteins of the TIM (T cell immunoglobulin and mucin domain) family have emerged recently as important regulators of immune function. However, virtually nothing is known about the signal transduction mechanisms used by these proteins. We have been particularly interested in understanding the function and regulation of TIM-1, which is expressed preferentially by Th2 effector cells. Extracellular polymorphisms in both human and murine TIM-1 are strongly associated with susceptibility or resistance to the development of asthma. We and others have recently found that TIM-1 can enhance T cell activation and differentiation. TIM-1 expression augments the activation of signaling pathways that target the NFAT and AP-1 transcription factors and appears to lead to a preferential skewing of T cells to the Th2 lineage. Furthermore, we have found that TIM-1 co-stimulatory signaling is mediated by a conserved tyrosine contained within its cytoplasmic tail. We hypothesize that expression of TIM-1 enhances T cell activation and polarization of helper T cells to the Th2 lineage, through phosphotyrosine-dependent co-stimulatory signaling that enhances induction of NFAT and AP-1. We will test this hypothesis with three specific aims.
In Aim 1, we will identify the mechanisms underlying TIM-1's effects on helper T cell differentiation.
In Aim 2, we will identify the kinase(s) responsible for phosphorylation of TIM-1 Y276, signaling proteins recruited to that site and the role of Y276 in vivo through the generation of a Y276F knock-in mouse model.
In Aim 3, we will determine the effects of TIM-1 on cytoplasmic signaling pathways that regulate NFAT and AP-1. Relevance: Allergic asthma develops as the result of inappropriate immune responses to environmental antigens. Completion of the experiments outlined in this proposal will lead to a more complete understanding of a novel cell surface molecule, TIM-1, that has been implicated in immune function and susceptibility to asthma. Such knowledge may result in the identification of novel targets for therapy and/or diagnosis of asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067544-04
Application #
7776828
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Davidson, Wendy F
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$283,380
Indirect Cost
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lin, Jean; Chen, Leo; Kane, Lawrence P (2012) Murine Tim-1 is excluded from the immunological synapse. F1000Res 1:10
Lee, J; Phong, B; Egloff, A M et al. (2011) TIM polymorphisms--genetics and function. Genes Immun 12:595-604
Lin, J; Kane, L P (2011) Are TIM proteins involved in asthma development or pathology? Clin Exp Allergy 41:917-9
Lee, Judong; Su, Ee Wern; Zhu, Chen et al. (2011) Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol Cell Biol 31:3963-74
Su, Ee W; Bi, Shuguang; Kane, Lawrence P (2011) Galectin-9 regulates T helper cell function independently of Tim-3. Glycobiology 21:1258-65
Kane, Lawrence P (2010) T cell Ig and mucin domain proteins and immunity. J Immunol 184:2743-9
Ho, Allen W; Shen, Fang; Conti, Heather R et al. (2010) IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail. J Immunol 185:1063-70
de Souza, Anjali J; Oak, Jean S; Jordanhazy, Ryan et al. (2008) T cell Ig and mucin domain-1-mediated T cell activation requires recruitment and activation of phosphoinositide 3-kinase. J Immunol 180:6518-26
Su, Ee Wern; Lin, Jean Y; Kane, Lawrence P (2008) TIM-1 and TIM-3 proteins in immune regulation. Cytokine 44:9-13