Abnormal CTLA-4 function in T cells from patients with systemic lupus erythematosus
| Autor: | Fabian Flores-Borja, Hardeep S Kalsi, Mark N. Lazarus, Michael R. Ehrenstein, Claudia Mauri, Elizabeth C. Jury, David A. Isenberg |
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| Rok vydání: | 2010 |
| Předmět: |
CD4-Positive T-Lymphocytes
CD3 Complex T-Lymphocytes CD3 Immunology chemical and pharmacologic phenomena Biology Lymphocyte Activation Membrane Microdomains CD28 Antigens Antigens CD medicine Humans Lupus Erythematosus Systemic Immunology and Allergy CTLA-4 Antigen skin and connective tissue diseases Autoimmune disease Microscopy Confocal Lupus erythematosus Systemic lupus erythematosus ZAP70 CD28 FOXP3 Forkhead Transcription Factors hemic and immune systems Flow Cytometry medicine.disease CTLA-4 biology.protein |
| Zdroj: | European Journal of Immunology. 40:569-578 |
| ISSN: | 1521-4141 0014-2980 |
| Popis: | CTLA-4 is a critical gatekeeper of T-cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA-4 in SLE. Our results reveal increased CTLA-4 expression in FOXP3(-) responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA-4 was unable to regulate T-cell proliferation, lipid microdomain formation and phosphorylation of TCR-zeta following CD3/CD28 co-stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co-stimulation, there was no parallel increase in CTLA-4 expression, which would normally provide a break on T-cell proliferation. These defects were associated with exclusion of CTLA-4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA-4 dysfunction as a potential cause for abnormal T-cell activation in patients with SLE, which could be targeted for therapy. |
| Databáze: | OpenAIRE |
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