title: The IL-7Rα pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis.
abstract: The IL-7Rα single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Rα 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-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls (HC). 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 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-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.
authors.affiliation: Department of Neurology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Karim L
authors.initials: KL
authors.lastname: Kreft
authors.forename: Evert
authors.initials: E
authors.lastname: Verbraak
authors.forename: Annet F
authors.initials: AF
authors.lastname: Wierenga-Wolf
authors.forename: Marjan
authors.initials: M
authors.lastname: van Meurs
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Rogier Q
authors.initials: RQ
authors.lastname: Hintzen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D053804:Granzymes / Q000096:biosynthesis; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015851:Interleukin-7; D008565:Membrane Proteins; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; C415350:interleukin-7 receptor, alpha chain; D053804:Granzymes