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

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.