Altered CD45 isoform expression in C77G carriers influences cytokine responsiveness and adhesion properties of T cells.
The C77G polymorphism in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of C77G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, hepatitis C and human immunodeficiency virus (HIV)-1. C77G individuals overexpress CD45RA isoforms on activated/memory T cells. We have shown previously that aberrant expression of CD45RA isoforms enhances the intensity of T cell receptor (TCR) signalling. Here we report that the C77G polymorphism also influences the responsiveness of T cells to cytokines and alters their adhesion properties. When stimulated by interleukin (IL)-2, C77G T cells proliferated more strongly than wild-type controls and showed accelerated phosphorylation of Janus kinase (Jak1). Furthermore, C77G T cells exhibited a higher tendency to form homotypic aggregates in culture which could be enhanced significantly by antibody-mediated triggering of the variant CD45RA molecules. These data indicate that the changes in CD45 isoform combination resulting from C77G may not only affect TCR signalling but also cytokine-driven T cell responses and cellular adhesion. Altered immune responsiveness may enhance susceptibility of C77G carriers for certain diseases.
Windhagen
A
A
Abteilung Neurologie, Medizinische Hochschule Hannover, Hannover, Germany.
Sönmez
D
D
Hornig-Do
H T
HT
Kalinowsky
A
A
Schwinzer
R
R
D000328:Adult; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D006579:Heterozygote; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000097:blood / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D007376:Interleukin-2; D020033:Protein Isoforms; D017493:Leukocyte Common Antigens