title: Modulation of peripheral T-cell function by interleukin-7 in rheumatoid arthritis.
abstract: BACKGROUND
  Interleukin-7 (IL-7) is a cytokine essential for T-cell lymphopoiesis, survival and polarization with an emerging role in autoimmunity. We previously demonstrated reduced levels of circulating IL-7 in rheumatoid arthritis (RA), although high amounts are expressed in joints, suggesting differences between systemic and synovial effects. We observed healthy levels of IL-7 in 48% of RA patients in clinical remission (CR) and aimed to investigate the consequences of IL-7 deficiency on T-cell responses.
  
  
  METHODS
  We used RA patients with active disease and in CR presenting various levels of IL-7, to investigate its modulatory effects on T cells by analysing responses to phyto-haemagglutinin (PHA), expression of polarization or survival factors, or suppression by regulatory T cells (Tregs).
  
  
  RESULTS
  IL-7 levels were normal (>10 pg/ml) in 48% of RA patients in CR. Amongst 63 CR patients followed up for 18 months, lack of IL-7 recovery was observed in 13 out of 15 (86%) patients experiencing relapse but only 11 out of 48 (23%) of those who did not (P = 0.0002). Binary regressions showed high significance for below normal IL-7 levels for self-reported maternal family history of arthritis (odds ratio (OR): 7.66, P = 0.006) and a trend for smoking (OR: 3.33, P = 0.068) with no further demographic or clinical associations. Serum IL-7 correlated with restored CD4+T-cell response to PHA (rho = 0.879); this was not related to an increase in T-cell proliferation capacity or expression of survival factors B-cell lymphoma 2 (BCL2) and BCL2-associated protein X (BAX). Expression of Th1 polarization factor (TBET) was also dependent on exposure to IL-7 in vivo (rho = 0.600). In contrast CD25highTregs' response to PHA was not affected by in vivo IL-7, but their suppression capabilities were related to circulating IL-7 (rho = 0.589). Co-stimulation with IL-7 (mimicking the joint environment) increased responsiveness of CD4+T-cells to PHA, lowering the ability of CD25highTregs to suppress them.
  
  
  CONCLUSIONS
  Our data demonstrate that IL-7 has a critical role in modulating T-cell function in vivo, possibly explaining opposing effects observed systemically and in the joint. Lack of IL-7 recovery in CR by maintaining a suppressed immune system may be a determinant factor in the occurrence of relapse.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Churchman
authors.forename: Jehan J
authors.initials: JJ
authors.lastname: El-Jawhari
authors.forename: Agata N
authors.initials: AN
authors.lastname: Burska
authors.forename: Rekha
authors.initials: R
authors.lastname: Parmar
authors.forename: Vincent
authors.initials: V
authors.lastname: Goëb
authors.forename: Philip G
authors.initials: PG
authors.lastname: Conaghan
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Frederique
authors.initials: F
authors.lastname: Ponchel
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis*; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D015851:Interleukin-7 / Q000008:administration & dosage / Q000097:blood*; D008297:Male; D008875:Middle Aged; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D015851:Interleukin-7