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The 77CG 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 Sclerosis¹

Hue-Tran Do^*, Wiebke Baars^*, Katja Borns^*, Anja Windhagen and Reinhard Schwinzer^2,*

^* Transplantationslabor, Klinik für Viszeral-und Transplantationschirurgie and Neurologie, Medizinische Hochschule, Hannover, Germany

The 77CG mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77CG 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 77CG 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 p56^lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR- and an enhanced Ca²⁺ flux to TCR/CD3 stimulation. These data suggest that 77CG may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.