The IL-7Ra Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

The IL-7Ra single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Ra is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Ra expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7Ra + CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Ra membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7Ra + CD8 + and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8 + IL-7Ra + in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Ra + lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7–induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A. M ultiple sclerosis (MS) is a complex disease, presumed to be autoimmune mediated. The exact etiology is unknown , but a combination of genetic and environmental factors, including infections, is important in the development of the disease (1). Extensive research has focused on the role of CD4 + T cell subsets, notably Th1 and Th17 cells. However, recently increasing evidence for an important role of Ag-specific CD8 + cytotoxic T cells has emerged (2, 3). For several decades, the only genetic association with an increased risk to develop MS was the class II HLA allele DRB1*15:01 (4). Recently, a protective effect of the HLA class I allele HLA A*02:01 has been shown and some additional HLA class I protective alleles have been suggested (5). Although many genetic studies have been performed, very few non-HLA genetic factors were found to be associated with MS. However, the International Multiple Sclerosis Genetics Consortium published …