The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis
Copyright policy )The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis
Abstract The 77C→G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C→G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C→G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-ζ and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C→G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.
- Hochschule Hannover Germany
Heterozygote, Isoantigens, Multiple Sclerosis, Base Sequence, T-Lymphocytes, Receptors, Antigen, T-Cell, Antibodies, Monoclonal, DNA, In Vitro Techniques, Cell Line, Case-Control Studies, Humans, Leukocyte Common Antigens, Point Mutation, Immunologic Memory, Signal Transduction
Heterozygote, Isoantigens, Multiple Sclerosis, Base Sequence, T-Lymphocytes, Receptors, Antigen, T-Cell, Antibodies, Monoclonal, DNA, In Vitro Techniques, Cell Line, Case-Control Studies, Humans, Leukocyte Common Antigens, Point Mutation, Immunologic Memory, Signal Transduction
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