Generation of a normal peripheral T cell repertoire requires that T cell precursors proliferate, differentiate, and migrate through thymic stroma while surviving rigorous selective pressures. Recent work has shed light upon the complex molecular bases of pre-T cell migration and both positive and negative selection of immature T cells. Signaling through the T cell antigen receptor (TCR) and pre-TCR is required for selection and is dependent upon the function of numerous molecular intermediates, including members of a group of scaffolding or adapter proteins. Several adapters, including SLP-76 and LAT, play critical and non-redundant roles in thymocyte selection. One SLP-76-associated molecule, Adhesion and Degranulation-promoting Adapter Protein (ADAP), is an hematopoietic-specific adapter protein previously shown to play key roles in mature T cell adhesion, integrin activation, and activation. Preliminary data now reveal that ADAP is also required for generation of normal T cell numbers, and for effective positive and negative selection. The mechanism of ADAP action in promoting thymocyte maturation is unknown. Experiments described in this proposal will test hypotheses that ADAP regulates thymocyte adhesion, motility, and proliferation and that ADAP functions to couple the TCR-dependent signaling machinery with actin cytoskeletal rearrangement. These investigations will probe the role of ADAP in murine thymocyte signaling and development using cell biologic, biochemical, and genetic techniques. Information gained from these studies will improve understanding of the biochemical mechanisms underlying crucial T cell developmental processes, and will likely provide new insight into potential targets for therapy of autoimmune or immune deficiency disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI056016-01
Application #
6673820
Study Section
Immunobiology Study Section (IMB)
Program Officer
Macchiarini, Francesca
Project Start
2003-07-01
Project End
2007-12-31
Budget Start
2003-07-01
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$148,500
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zou, Liangxing; Mendez, Felipe; Martin-Orozco, Natalia et al. (2008) Defective positive selection results in T cell lymphopenia and increased autoimmune diabetes in ADAP-deficient BDC2.5-C57BL/6 mice. Eur J Immunol 38:986-94
Burbach, Brandon J; Srivastava, Rupa; Medeiros, Ricardo B et al. (2008) Distinct regulation of integrin-dependent T cell conjugate formation and NF-kappa B activation by the adapter protein ADAP. J Immunol 181:4840-51
Medeiros, Ricardo B; Burbach, Brandon J; Mueller, Kristen L et al. (2007) Regulation of NF-kappaB activation in T cells via association of the adapter proteins ADAP and CARMA1. Science 316:754-8
Dluzniewska, Joanna; Zou, Liangxing; Harmon, Ian R et al. (2007) Immature hematopoietic cells display selective requirements for adhesion- and degranulation-promoting adaptor protein in development and homeostatsis. Eur J Immunol 37:3208-19
Mueller, Kristen L; Thomas, Molly S; Burbach, Brandon J et al. (2007) Adhesion and degranulation-promoting adapter protein (ADAP) positively regulates T cell sensitivity to antigen and T cell survival. J Immunol 179:3559-69