Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility

Brain. 2011 Mar;134(Pt 3):693-703. doi: 10.1093/brain/awr010.


The tyrosine kinase 2 variant rs34536443 has been established as a genetic risk factor for multiple sclerosis in a variety of populations. However, the functional effect of this variant on disease pathogenesis remains unclear. This study replicated the genetic association of tyrosine kinase 2 with multiple sclerosis in a cohort of 1366 French patients and 1802 controls. Furthermore, we assessed the functional consequences of this polymorphism on human T lymphocytes by comparing the reactivity and cytokine profile of T lymphocytes isolated from individuals expressing the protective TYK2(GC) genotype with the disease-associated TYK2(GG) genotype. Our results demonstrate that the protective C allele infers decreased tyrosine kinase 2 activity, and this reduction of activity is associated with a shift in the cytokine profile favouring the secretion of Th2 cytokines. These findings suggest that the rs34536443 variant effect on multiple sclerosis susceptibility might be mediated by deviating T lymphocyte differentiation toward a Th2 phenotype. This impact of tyrosine kinase 2 on effector differentiation is likely to be of wider importance because other autoimmune diseases also have been associated with polymorphisms within tyrosine kinase 2. The modulation of tyrosine kinase 2 activity might therefore represent a new therapeutic approach for the treatment of autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Cell Proliferation
  • Cells, Cultured
  • Chi-Square Distribution
  • Cytokines / metabolism
  • Female
  • Flow Cytometry
  • France / epidemiology
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Male
  • Models, Molecular
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / pathology*
  • Polymorphism, Single Nucleotide / genetics*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology*
  • TYK2 Kinase / genetics*
  • Time Factors
  • Young Adult


  • Cytokines
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • TYK2 Kinase