Dendritic cells require NIK for CD40-dependent cross-priming of CD8 ⁺ T cells

Abstract

Dendritic cells (DCs) link innate and adaptive immunity and use a host of innate immune and inflammatory receptors to respond to pathogens and inflammatory stimuli. Although DC maturation via canonical NF-κB signaling is critical for many of these functions, the role of noncanonical NF-κB signaling via the serine/threonine kinase NIK (NF-κB-inducing kinase) remains unclear. Because NIKdeficient mice lack secondary lymphoid organs, we generated transgenic mice with targeted NIK deletion in CD11c + cells. Although these mice exhibited normal lymphoid organs, they were defective in cross-priming naive CD8+ T cells following vaccination, even in the presence of anti-CD40 or polyinosinic:polycytidylic acid to induce DC maturation. This impairment reflected two intrinsic defects observed in splenic CD8+ DCs in vitro, namely antigen cross-presentation to CD8+ T cells and secretion of IL-12p40, a cytokine known to promote cross-priming in vivo. In contrast, antigen presentation to CD4 + T cells was not affected. These findings reveal that NIK, and thus probably the noncanonical NF-κB pathway, is critical to allow DCs to acquire the capacity to cross-present antigen and prime CD8 T cells after exposure to licensing stimuli, such as an agonistic anti-CD40 antibody or Toll-like receptor 3 ligand.NIK | dendritic cells | CD8 T cells | cross-priming | antigen cross-presentation

30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology

“…The phenotype of patients was different from the NIK knockout mouse because it lacked the severe structural defects in lymph nodes, Peyer’s patches, splenic and thymic structures found in the latter (Yin et al, 2001). Nonetheless, bone marrow chimeras and conditional lymphocyte knockout mouse models recapitulated the patient phenotype, including decreased memory T cells, disrupted B cell maturation and activation, and defective DCs and NK cells (Brightbill et al, 2015; Katakam et al, 2015; Noma et al, 2015; Rowe et al, 2013). These results imply that NIK action in non-hematopoietic tissues is crucially different in humans and mice.…”

Cellular and molecular regulation of innate inflammatory responses

“…While Rab11a activity recruits and keeps MHC-I within endosomal recycling compartment (ERC) under steady condition, MyD88-dependent TLR signals drive IKK2-mediated phosphorylation of phagosome-associated SNAP23, orchestrating ERC-phagosome fusion, promoting enrichment of phagosomes with ERC-derived MHC-I, and finally allowing cross-presentation during infection. 139 Transcription factor TFEB, 140 cell stress sensor IRE-1α, [141][142][143] NF-κB-inducing kinase (NIK) 144 and the lectin Siglec-G 145 have been shown to regulate DC cross-presentation in initiating antigen-specific CTL responses via distinct molecular mechanisms. For example, Siglec-G inhibits cross-presentation by CD8α+ DC via impairing the formation of the MHC class I-exogenous antigen peptide complex, contributing to suppression of CTL responses to intracellular bacterial infection with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin and tumors.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[2][3][4][48][49][50][51] On the other side, malignant cells succumbing to a putative ICD inducer can be fed to dendritic cells (DCs), 2,44,52-55 followed by (1) phagocytosis assays [56][57][58][59][60][61][62] ; (2) assessment of activation markers on the DC surface (e.g., CD80, CD86, MHC Class II) and functional markers in conditioned media (e.g., interleukin-6 or IL6, IL1b, IL12p70) 54,[63][64][65][66][67][68][69][70][71][72] priming assays with syngeneic lymphocytes. [73][74][75][76][77][78][79][80][81] Although none of these assays (alone or in combination) can reliably predict the ability of a specific intervention to cause ICD, the use of surrogate approaches is highly convenient for screening purposes or when studies are focused on the human model. 2,3,44,48,82 A number of mechanisms regulate the capacity of a particular agent to drive bona fide ICD and the ability of the host to perceive such an instance of cell death as immunogenic, and hence respond with potentially curative TAA-specific adaptive immunity.…”