A polymorphism in the human cytotoxic T-lymphocyte antigen 4 ( CTLA4) gene (exon 1 +49) alters T-cell activation.
The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an important modifier of T-cell activation with down-regulatory properties upon B7 engagement. An allelic polymorphism in exon 1 of the CTLA4 gene coding for the peptide leader sequence of CTLA4 was recently described. This polymorphism was detected in association with several autoimmune diseases. In this study, we investigated the functional impact of the CTLA4 exon 1 +49 A/G dimorphism on T-cell activation and cellular localization. We examined the T-cell response from healthy donors either homozygous for A or G at position +49 of the exon 1. Under suboptimal stimulation conditions we found a greater proliferative response of cells from donors homozygous for G at position +49. FACS analysis of CTLA4 expression revealed a reduced up-regulation of CTLA4 from G/G donors upon T-cell activation, if compared with wild-type cells. Intracellular CTLA4 distribution demonstrated qualitatively different staining patterns between the two genotypes as determined using confocal fluorescence microscopy. Our results suggest that the G allele at position +49 of exon 1 affects the CTLA4-driven down-regulation of T-cell activation and may be an important factor in the pathogenesis of autoimmune diseases.
Mäurer
Mathias
M
Department of Neurology, Bayerische Julius-Maximilians Universität, Josef-Schneider Strasse 11, 97080 Würzburg, Germany. matthias.maurer@mail.uni-wuerzburg.de
Loserth
Silke
S
Kolb-Mäurer
Annette
A
Ponath
Anke
A
Wiese
Stefan
S
Kruse
Niels
N
Rieckmann
Peter
P
D000069594:Abatacept; D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis / Q000235:genetics*; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D005091:Exons; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007376:Interleukin-2; D012333:RNA, Messenger; D000069594:Abatacept