Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice
| Autor: | Xiaoxi Chen, Hung-Sia Teh, Michael T. Chow, John J. Priatel |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Immunology Cell Receptors Antigen T-Cell chemical and pharmacologic phenomena Spleen Thymus Gland CD8-Positive T-Lymphocytes Oncogene Protein p21(ras) Lymphocyte Activation T-Lymphocytes Regulatory Mice Antigens CD Internal medicine medicine Animals Guanine Nucleotide Exchange Factors Immunology and Allergy IL-2 receptor Cell Proliferation Mice Knockout Mitogen-Activated Protein Kinase Kinases biology Cell growth Lymphopoiesis CD44 T-cell receptor FOXP3 hemic and immune systems Interleukin-10 Cell biology medicine.anatomical_structure Endocrinology Son of Sevenless Proteins Mutation biology.protein CD8 Signal Transduction |
| Zdroj: | The Journal of Immunology. 180:5973-5982 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.180.9.5973 |
| Popis: | RasGRP1 and Sos are two Ras-guanyl-nucleotide exchange factors that link TCR signal transduction to Ras and MAPK activation. Recent studies demonstrate positive selection of developing thymocytes is crucially dependent on RasGRP1, whereas negative selection of autoreactive thymocytes appears to be RasGRP1 independent. However, the role of RasGRP1 in T regulatory (Treg) cell development and function is unknown. In this study, we characterized the development and function of CD4+CD25+Foxp3+ and CD8+CD44highCD122+ Treg lineages in RasGRP1−/− mice. Despite impaired CD4 Treg cell development in the thymus, the periphery of RasGRP1−/− mice contained significantly increased frequencies of CD4+Foxp3+ Treg cells that possessed a more activated cell surface phenotype. Furthermore, on a per cell basis, CD4+Foxp3+ Treg cells from mutant mice are more suppressive than their wild-type counterparts. Our data also suggest that the lymphopenic environment in the mutant mice plays a dominant role of favored peripheral development of CD4 Treg cells. These studies suggest that whereas RasGRP1 is crucial for the intrathymic development of CD4 Treg cells, it is not required for their peripheral expansion and function. By contrast to CD4+CD25+Foxp3+ T cells, intrathymic development of CD8+CD44highCD122+ Treg cells is unaffected by the RasGRP1−/− mutation. Moreover, RasGRP1−/− mice contained greater numbers of CD8+CD44highCD122+ T cells in the spleen, relative to wild-type mice. Activated CD8 Treg cells from RasGRP1−/− mice retained their ability to synthesize IL-10 and suppress the proliferation of wild-type CD8+CD122− T cells, albeit at a much lower efficiency than wild-type CD8 Treg cells. |
| Databáze: | OpenAIRE |
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