Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions

Background Drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (Di HS / DRESS ) is a distinct phenotype of severe drug eruptions characterized by sequential reactivations of herpesviruses. Although a progressive loss of suppressive function in regulatory T cells (Tregs) occurred during the course of DiHS / DRESS , but not in Stevens‐Johnson syndrome/toxic epidermal necrolysis ( SJS / TEN ), no previous studies investigated the mechanism. Given the recent finding that Treg development could be differentially regulated by CD 16 + patrolling monocytes ( pMO s) and CD 14 + classical monocytes ( cMO s), we can hypothesize that a differential fine‐tuned interaction between Tregs and monocytes is the driving force behind the possible shift from Tregs to Th17 cells over a prolonged period of time in Di HS /DRESS. Objective To investigate whether the shift from Treg to Th17 could specifically occur during the course of Di HS / DRESS and to elucidate which subsets of monocytes could be involved in the shift. Methods We performed a prospective longitudinal study on the frequencies of Tregs, Th17 cells and monocyte subsets after onset of Di HS / DRESS and SJS / TEN , and long after their clinical resolutions. We next examined whether pMO s and cMO s could have a strong impact on the Th17/Treg differentiation and which cytokines could be crucial for the interaction between Th17/Tregs and MO subsets, by in vitro cocultures. Results Selective depletion of pMO s occurring at the acute stage of Di HS / DRESS was associated with the relative increase in the frequencies of cMO s producing IL ‐10 and it did drive Treg expansions. After clinical resolution, pMO s producing IL ‐6 were alternatively recruited and contributed to the eventual shift from a Treg to Th17 responses. Conclusions and Clinical Relevance The gradual shift from Treg to Th17 cell development observed during the clinical course of Di HS / DRESS is mediated by the predominance of cMO s at the acute stage and alternatively recruited pMO s at the resolution stage, respectively.