Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses.
The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context.
Hermiston
Michelle L
ML
Department of Pediatrics, Medicine, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Zikherman
Julie
J
Tan
Allison L
AL
Lam
Viola C
VC
Cresalia
Nicole M
NM
Oksenberg
Nir
N
Goren
Nira
N
Brassat
David
D
Oksenberg
Jorge R
JR
Weiss
Arthur
A
D000818:Animals; D015551:Autoimmunity; D002118:Calcium / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000235:genetics*; D051379:Mice; D017354:Point Mutation / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology
D011948:Receptors, Antigen, T-Cell; D017493:Leukocyte Common Antigens; D002118:Calcium