The antigen specific cells of the immune system, the T and B-lymphocytes, express multi-subunit cell surface receptors (TCR and BCR) that are essential for recognizing and responding to pathogens such as viruses, bacteria, and parasites. T cells have one intriguing feature in that each TCR recognizes a complex containing a small pathogen-derived peptide and a much larger self-protein termed the major histocompatibility complex (MHC). My laboratory has been elucidating how the TCR can discriminate between self-peptides versus foreign peptides bound to the MHC. Effective TCR signaling will elicit diverse biological outcomes such as lymphokine release and cytotoxic functions. Incomplete or attenuated signals may promote T cell death, and in the thymus, may be important for the development of the T cell repertoire. This has led us to an analysis of the intracellular signaling processes regulated by the different TCR subunits. We have been examining the functional roles of the cytoplasmic domains of the CD3 zeta and CD3 epsilon subunits of the TCR complex. The domains interact with families of kinases and phosphatases.
We are currently pursuing several related questions.
1) The CD3 zeta subunit contains three copies of a signaling domain called the ITAM. These are tyrosine phosphorylated following TCR/ligand interactions. We have used transgenic and knockout mice to elucidate the functions of two phosphorylated forms of zeta termed p21 and p23.
2) The CD3 epsilon subunit contains several signaling domains including the ITAM and a proline-rich stretch. We have discovered recently a novel domain termed the basic rich stretch (BRS). This motif interacts with a serine/threonine kinase termed GRK2. We are addressing the role of this domain using transgenic and knockout mice. Our specific questions are whether this BRS-GRK2 interaction regulates T cell functions and T cell responses to chemokines.
3) The ITAMs of the TCR complex are transiently phosphorylated following TCR signaling. We used a large-scale screen and identified a protein tyrosine phosphatase family that could dephosphorylate the phospho-ITAMs. To elucidate their contributions to biology, we have made a knockout mouse of one. We are currently characterizing this mouse line
A second project in the laboratory pertains to tuberculosis. We are developing presently a large-scale screen to identify M. tuberculosis-encoded genes that suppress innate and/or adaptive immune responses.
RESEARCH INTERESTS
Immunology
Infectious Diseases
T cell development
Signal Transduction
Protein tyrosine kinases and phosphatases
RECENT PUBLICATIONS
Pitcher, L.A.,Mathis, M.A.,Young, J. A., DeFord, L.M., Purtic, B., Wulfing, C., van Oers, N.S.C., "The CD3 ge/de signaling module provides normal T cell functions in the absence of the TCR z-ITAMs" Eur. J. immunol., In Press December 2005
Pitcher, L. A.,Mathis, M. A., Subramanian, S., Young, J. A., Wakeland, E. K., Love, P. E.,van Oers, N. S., "Selective Expression of the 21-Kilodalton Tyrosine-Phosphorylated Form of TCR {zeta} Promotes the Emergence of T Cells with Autoreactive Potential" J Immunol, 174:6071-9, May 2005
Purtic, B., Pitcher, L. A., van Oers, N. S., Wulfing, C., "T cell receptor (TCR) clustering in the immunological synapse integrates TCR and costimulatory signaling in selected T cells" Proc Natl Acad Sci U S A, 102:2904-9, February 2005
DeFord-Watts, L.A., Young, J. A.,Pitcher, L. A.,van Oers, N. S., "The Membrane-proximal Portion of CD3 {epsilon} Associates with the Serine/Threonine Kinase GRK2" J. Biol. Chem., 282:16126-16134, June 2007
Becker, A.M., Deford-Watts, L. M, Wuelfing, C., van Oers, N.S.C., "The Constitutive Tyrosine Phosphorylation of CD3{zeta} Results from TCR-MHC Interactions That Are Independent of Thymic Selection" Journal of Immunology, 4120-8178, April 2007
SIGNIFICANT PUBLICATIONS
Becker, A. M.,Deford-Watts, L. M.,Wuelfing, C.,van Oers, N. S., "The Constitutive Tyrosine Phosphorylation of CD3{zeta} Results from TCR-MHC Interactions That Are Independent of Thymic Selection" Journal of Immunology, 178:4120-8, April 2007
DeFord-Watts, L.A., Young, J. A.,Pitcher, L. A.,van Oers, N. S., "The Membrane-proximal Portion of CD3 {epsilon} Associates with the Serine/Threonine Kinase GRK2" J. Biol. Chem., 282:16126-34, June 2007
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