title: The interleukin-7 receptor α chain contributes to altered homeostasis of regulatory T cells in multiple sclerosis.
abstract: Treg homeostasis is disturbed in multiple sclerosis (MS). Frequencies of recent thymic emigrant (RTE)-Treg are reduced and the disparity between RTE-Treg and long-lived memory Treg coincides with the MS-associated Treg defect, as shown previously. Recent studies demonstrate that IL-7 and thymic stromal lymphopoietin (TSLP) are critical for Treg maturation. Therefore, altered signaling through their receptors (IL-7R, TSLP receptor (TSLPR)), sharing the IL-7Rα-chain (IL-7Rα), might contribute to impaired Treg development. Using blood samples from 56 patients with MS and 33 healthy controls, we assessed IL-7Rα-expression on conventional T cells; frequencies, phenotypes and suppressive activities of Treg, plasma levels of IL-7 and soluble IL-7Rα; and screened for MS-associated IL-7RA gene polymorphism rs6897932. Moreover, we determined Treg expressing two different TCR Vα-chains designating thymus-originated cells. As TSLP/TSLPR signaling in thymic myeloid dendritic cells (MDCs) promotes Treg differentiation, we measured TSLPR expression on peripheral MDCs to indirectly test whether altered TSLPR expression might add to compromised Treg neogenesis. We found reduced IL-7Rα expression on conventional T cells and upregulated IL-7 plasma levels together with reduction of RTE-Treg frequencies and Treg function in MS, without clear genetic influence. Decreased IL-7Rα expression in MS correlated with declined dual-receptor-Treg and reduced MDC TSLPR expression, indicating contracted thymic Treg output. We suggest that altered IL-7R/TSLPR signaling contributes to impaired Treg neogenesis in MS, which is compensated by expanded memory-Treg and finally results in dysfunctional Treg.
authors.affiliation: Division of Molecular Neuroimmunology, Department of Neurology, University Hospital of Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.forename: Mirjam
authors.initials: M
authors.lastname: Korporal
authors.forename: Alexander
authors.initials: A
authors.lastname: Schwarz
authors.forename: Bettina
authors.initials: B
authors.lastname: Balint
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wildemann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006706:Homeostasis; D006801:Humans; D015851:Interleukin-7 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult; D000094632:Thymic Stromal Lymphopoietin
chemical_list: C498762:CRLF2 protein, human; D016207:Cytokines; C508605:IL7 protein, human; D015851:Interleukin-7; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018121:Receptors, Cytokine; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000094632:Thymic Stromal Lymphopoietin