Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, Hintzen RQ. The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis. J Immunol. 2012 Jan [Epub ahead of print]
The interleukin 7 receptor alpha chain (IL-7Rα) single nucleotide polymorphism rs6897932 is associated with an increased genetic risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell function, proliferation, and anti-apoptotic 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-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls. A significantly higher frequency of IL-7Rα(+) CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα 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-7Rα(+)CD8(+) and rs6897932 risk allele carriership.
Upon IL-7 stimulation, MS patients had stronger STAT5 (a transcription factor) activation in CD8EM compared with Healthy controls. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B (a protein that punches holes in its target. Imagine a pin prick to a balloon this is what granzymes can do to virally infected cells) between MS and HC. Stainings of different lesions in post-mortem MS brain material showed expression of IL-7 and CD8(+)IL-7Rα(+) in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα(+) 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.
Variants in Interleukin seven receptor are associated with an increase risk of developing MS. We know that interleukin 7 is associated with the function of the immune system but how does the variant affect MS?. This study does not answer this question as the expression of IL-7R on T cells did not correlate with the variant of IL-7R genes, but it does suggest that cells expressing IL-7R are part of the disease process. There was more IL-7R on T cells from people with MS compared with healthy people and cells expressing this molecule accumlate in early MS lesions.