Abnormalities in iNKT cells are associated with impaired ability of monocytes to produce IL-10 and suppress T-cell proliferation in sarcoidosis.
Sarcoidosis is a multisystem granulomatous disorder characterized by marked T-cell expansion of T helper 1 (Th1) cells. The cause of T-cell overactivity is unknown. We hypothesized that interleukin-10 (IL-10) production by a yet undefined cell type might be defective, resulting in loss of regulation of T-cell activity. Focusing on IL-10-producing monocytes, we first showed that monocytes isolated from the peripheral blood of corticosteroid-naïve sarcoidosis patients (n = 51) produced less IL-10 compared to controls, and were less able to suppress T-cell proliferation. In addition, monocytic IL-10 production correlated negatively with disease activity score. As invariant natural killer T (iNKT) cells are known to both interact with monocytes and be reduced in sarcoidosis patients, we then asked whether iNKT-specific defects might be responsible for this reduced IL-10 production. We found that greater numbers of circulating iNKT cells was associated with higher IL-10 production. Moreover, iNKT cells enhanced monocytic IL-10 production in vitro. Defective IL-10 production and T-cell suppression by sarcoidosis monocytes could be restored following their coculture with iNKT cells, in a CD1d- and cell contact-dependent process. We suggest that reduced iNKT-cell numbers in sarcoidosis may lead to impaired monocytic IL-10 production and unchecked T-cell expansion in sarcoidosis. These findings provide fresh insight into the mechanism of sarcoidosis disease, and interaction between iNKT cells and monocytes.
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, UK.
Anjali
A
Crawshaw
Yvonne R
YR
Kendrick
Andrew J
AJ
McMichael
Ling-Pei
LP
Ho
D000328:Adult; D002450:Cell Communication; D049109:Cell Proliferation; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000502:physiology*; D012507:Sarcoidosis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
C508609:IL10 protein, human; D016753:Interleukin-10
IL-10; Invariant natural killer T (iNKT) cells; Monocytes; Sarcoidosis; T-cell proliferation