Abnormalities in iNKT cells are associated with impaired ability of monocytes to produce IL‐10 and suppress T‐cell proliferation in sarcoidosis

Abstract

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.

Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis

“…Cranshaw et al . reported that sarcoidosis monocytes had reduced IL-10 production11. In the whole blood assay used in the present study, we did not demonstrate that the IL-10 regulatory axis was dysfunctional in sarcoidosis, and the expression profiles of regulatory SIRP-α/CD47 were also similar between sarcoidosis and healthy subjects.…”

“…The choice of methods for cell isolation and stimulation could explain the differences in the findings, since Cranshaw et al . studied monocytes that had been isolated by magnetic bead negative selection and stimulated with lipopolysaccharide11. Depending on the nature of the stimulant or other factors, deficiencies in more than one monocyte regulatory pathway may contribute to immune hyper-activation in sarcoidosis.…”

“…Cranshaw et al . reported that sarcoidosis blood monocytes produced smaller amounts of IL-10 than controls and were less able to suppress T cell proliferation11. Monocytes and macrophages also express signal-regulatory protein-alpha (SIRP-α) which binds to ubiquitously expressed CD47 and acts as an anti-phagocytic signal12, and CD200R13, which binds its cognate ligand CD200L on many cell types and leads to reduced mitogen-activated protein kinase signalling through recruitment of Ras GTPase activating protein14.…”

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

“…Sarcoidosis is a complex systemic granulomatous disorder of unknown etiology. Circulating monocytes op sarcoidosis patients produce less IL-10 ( 173 ), express more CD16 + ( 174 , 175 ), BAFF ( 166 ), TLR2 and TLR4 ( 176 ), IL-2R ( 177 ), adhesion molecules ( 178 ), produce more proinflammatory cytokines ( 176 , 179 – 181 ) and oxygen radicals ( 182 ), and have increased phagocytic activity ( 183 ), thus showing an increased activated phenotype ( 184 ). Moreover, monocytes of sarcoidosis patients are more likely to form giant cells ( 185 ).…”

Distinct immune regulatory receptor profiles linked to altered monocyte subsets in sarcoidosis

“…Understanding the cellular and molecular drivers of persistent and progressive sarcoidosis will be an important step towards identifying new targets for treatment. Chronic, nonresolving sarcoidosis is characterised immunologically by heightened inflammatory responses of tissue granuloma macrophages and their precursors, circulating blood monocytes (2,5,(10)(11)(12)(13)(14). Cell surface regulatory receptors such as CD200R serve to dampen inflammatory responses in monocytes and macrophages, including reducing production of TNF which is a key cytokine driving granuloma formation and persistence (15,16).…”