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.

• MeSH
• Lymphocyte Activation * drug effects   immunology   MeSH
• Cell Differentiation * drug effects   MeSH
• Cell Line MeSH
• Hepatitis A Virus Cellular Receptor 2 metabolism   MeSH
• CD8-Positive T-Lymphocytes * immunology   drug effects   MeSH
• Cytokines metabolism   MeSH
• Dendritic Cells * immunology   drug effects   metabolism   MeSH
• Imidazoles pharmacology   MeSH
• Humans MeSH
• Mast Cells * immunology   drug effects   metabolism   MeSH
• Monocytes immunology   drug effects   metabolism   MeSH
• Cell Proliferation * drug effects   MeSH
• Thapsigargin * pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hepatitis A Virus Cellular Receptor 2 MeSH
• Cytokines MeSH
• HAVCR2 protein, human MeSH Browser
• Imidazoles MeSH
• Thapsigargin * MeSH

X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.

• MeSH
• Apoptosis MeSH
• Crohn Disease genetics   pathology   MeSH
• Adult MeSH
• Humans MeSH
• Mutation MeSH
• Nod2 Signaling Adaptor Protein metabolism   MeSH
• Signal Transduction MeSH
• X-Linked Inhibitor of Apoptosis Protein metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• NOD2 protein, human MeSH Browser
• Nod2 Signaling Adaptor Protein MeSH
• X-Linked Inhibitor of Apoptosis Protein MeSH
• XIAP protein, human MeSH Browser