Impaired Proliferation of CD8+ T Cells Stimulated with Monocyte‐Derived Dendritic Cells Previously Matured with Thapsigargin‐Stimulated LAD2 Human Mast Cells

Abstract

CD8+ T cells are essential for adaptive immunity against infection and tumors. Their ability to proliferate after stimulation is crucial to their functionality. Dendritic cells (DCs) are professional antigen‐presenting cells that induce their proliferation. Here, we show that thapsigargin‐induced LAD2 mast cell (MC) line‐released products can impair the ability of monocyte‐derived DCs to induce CD8+ T‐cell proliferation and the generation of Th1 cytokine‐producing T cells. We found that culture medium conditioned with LAD2 MCs previously stimulated with thapsigargin (thapsLAD2) induces maturation of DCs as determined by the maturation markers CD80, CD83, CD86, and HLA‐DR. However, thapsLAD2‐matured DCs produced no detectable TNFα or IL‐12 during the maturation. In addition, although their surface expression of PD‐L1 was comparable with the immature or TLR7/8‐agonist (R848)‐matured DCs, their TIM‐3 expression was significantly higher than in immature DCs and even much higher than in R848‐matured DCs. In addition, contrary to R848‐matured DCs, the thapsLAD2‐matured DCs only tended to induce enhanced proliferation of CD4+ T cells than immature DCs. For CD8+ T cells, this tendency was not even detected because thapsLAD2‐matured and immature DCs comparably induced their proliferation, which contrasted with the significantly enhanced proliferation induced by R848‐matured DCs. Furthermore, these differences were comparably recapitulated in the ability of the tested DCs to induce IFNγ‐ and IFNγ/TNFα‐producing T cells. These findings show a novel mechanism of MC‐mediated regulation of adaptive immune responses.