The c.503T>C Polymorphism in the Human KLRB1 Gene Alters Ligand Binding and Inhibitory Potential of CD161 Molecules

Studying genetic diversity of immunologically relevant molecules can improve our knowledge on their functional spectrum in normal immune responses and may also uncover a possible role of different variants in diseases. We characterized the c.503T>C polymorphism in the human KLRB1 gene (Killer cell lectin-like receptor, subfamily B, member 1) coding for the cell surface receptor CD161. CD161 is expressed by subsets of CD4+ and CD8+ T cells and the great majority of CD56+ natural killer (NK) cells, acting as inhibitory receptor in the latter population. Genotyping a cohort of 118 healthy individuals revealed 40% TT homozygotes, 46% TC heterozygotes, and 14% carriers of CC. There was no difference in the frequency of CD161 expressing CD4+ and CD8+ T cells between the different genotypes. However, the frequency of CD161+ NK cells was significantly decreased in CC carriers as compared to TT homozygotes. c.503T>C causes an amino acid exchange (p.Ile168Thr) in an extracellular loop of the CD161 receptor, which is regarded to be involved in binding of its ligand Lectin-like transcript 1 (LLT1). Binding studies using soluble LLT1-Fc on 293 transfectants over-expressing CD161 receptors from TT or CC carriers suggested diminished binding to the CC variant. Furthermore, triggering of CD161 either by LLT1 or anti-CD161 antibodies inhibited NK cell activation less effectively in cells from CC individuals than cells from TT carriers. These data suggest that the c.503T>C polymorphism is associated with structural alterations of the CD161 receptor. The regulation of NK cell homeostasis and activation apparently differs between carriers of the CC and TT variant of CD161.