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CD3/CD46-mediated generation of IL-10-secreting T cells is defective in rheumatoid arthritis
  1. Gaelle Le Friec1,
  2. John Cardone1,
  3. Andrew Cope2,
  4. Claudia Kemper1
  1. 1MRC Centre for Transplantation, King's College School of Medicine, King's College London, London UK
  2. 2Academic Department of Rheumatology, King's College School of Medicine, King's College London, London UK


Background and objectives Control of effector T cell responses to foreign and self-antigens through interleukin (IL)-10-producing Th1 cells and adaptive IL-10+Tregs is vital for limiting immune pathology during infection and for preventing autoimmunity. However, the mechanisms that regulate their production remain incompletely understood. CD46 is the receptor for the C3b/C4b components of complement. The authors have previously demonstrated that activation of human CD4 T cells through the T-cell receptor and the complement regulator CD46 induces Tr1 like IL-10-producing Tregs. The authors set out to study factors that regulate the generation of IL-10 producing Tregs during normal immune homeostasis and to determine whether this pathway is defective in chronic inflammatory disease, such as rheumatoid arthritis.

Materials and methods CD4 T lymphocytes were purified from PBMC of normal donors or PBMC and synovial fluid of rheumatoid arthritis (RA) and JIA patients using CD4 MicroBeads prior to activation with anti-CD3 and anti-CD46 mAb in the presence or absence of increasing concentrations of IL-2. After 36 h cytokine production was determined using the Th1/Th2 cytokine bead array. Cells were stained using the IFNγ and IL-10 cytokine secretion assay kits in combination and IFNγ+, IFNγ+/IL-10+ and IL-10+ cells isolated via cell sorting. Supernatants from cultures of these cells were then tested for their capacity to suppress proliferation of freshly purified T cells. Approval for this study was obtained from the Local Ethics Review Committee.

Results IL-10-secreting T cells are derived from populations of differentiating Th1 effector T cells as they also secrete IFNγ. The authors observed that the cytokine expression profile of CD3/CD46-activated T cells is heavily influenced by the amount of IL-2 present during activation. Thus, in the presence of low IL-2, CD3/CD46-activation induces strong IFNγ-secretion and a proinflammatory effector phenotype. High IL-2 induces a ‘switch’ from IFNγ+ T cells, via an IFNγ+/IL-10+ state, to an IL-10+ phenotype. CD46-induced IFNγ+/IL-10+ and IL-10+ cells are suppressive. By contrast, analysis of T cell populations from patients with inflammatory arthritis such as RA and JIA reveals that progression to the IL-10+ state is blocked even in the presence of high exogenous IL-2. In addition, CD3/CD46-activated T cells produce 20–30 times more IFN-γ than IL-10.

Conclusions CD46 activation during T cell response initiation supports IFNγ secretion to combat infection while expansion of the effector response provides high IL-2 and the signal to switch to IL-10 production and resolution of the immune response. This regulatory switch appears to be defective in chronic inflammatory disease.

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