Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses
| Autor: | Allison L. Tan, Michelle L. Hermiston, Arthur Weiss, Nicole M. Cresalia, Nira Goren, Nir Oksenberg, Julie Zikherman, David Brassat, Jorge R. Oksenberg, Viola C. Lam |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Encephalomyelitis Autoimmune Experimental T cell T-Lymphocytes Phosphatase Receptors Antigen T-Cell Context (language use) Autoimmunity Protein tyrosine phosphatase Thymus Gland Biology medicine.disease_cause Mice Internal medicine medicine Animals Point Mutation Mutation Multidisciplinary T-cell receptor Biological Sciences Cell biology Endocrinology medicine.anatomical_structure Leukocyte Common Antigens Calcium Signal transduction Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 106(2) |
| ISSN: | 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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