Activated NKT Cells Can Condition Different Splenic Dendritic Cell Subsets To Respond More Effectively to TLR Engagement and Enhance Cross-Priming

Abstract

The function of dendritic cells (DCs) can be modulated through multiple signals, including recognition of pathogen-associated molecular patterns, as well as signals provided by rapidly activated leukocytes in the local environment, such as innate-like T cells. In this article, we addressed the possibility that the roles of different murine DC subsets in cross-priming CD8+ T cells can change with the nature and timing of activatory stimuli. We show that CD8α+ DCs play a critical role in cross-priming CD8+ T cell responses to circulating proteins that enter the spleen in close temporal association with ligands for TLRs and/or compounds that activate NKT cells. However, if NKT cells are activated first, then CD8α− DCs become conditioned to respond more vigorously to TLR ligation, and if triggered directly, these cells can also contribute to priming of CD8+ T cell responses. In fact, the initial activation of NKT cells can condition multiple DC subsets to respond more effectively to TLR ligation, with plasmacytoid DCs making more IFN-α and both CD8α+ and CD8α− DCs manufacturing more IL-12. These results suggest that different DC subsets can contribute to T cell priming if provided appropriately phased activatory stimuli, an observation that could be factored into the design of more effective vaccines.

Blockade of only TGF-β 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy

“…The vaccine used in this study contains a-GalCer, a well-characterized type I NKT (iNKT) cell agonist, as a molecular adjuvant, since a-GalCer has been reported to provide help to prime CD8 C T cells and facilitate cross-presentation of antigens to CD8 C T cells. [20][21][22] Therefore, in addition to conventional T cells, we also examined the changes in type I NKT cells in tumor draining lymph nodes ( Fig. 4).…”

“…a-GalCer has been shown by many studies not only to activate NKT cells to produce IFNg but also, as a result of type I NKT cell activation, to induce maturation of DCs and IL-12 production by DCs, and to facilitate cross-presentation of antigens by CD8a C DCs. 22,32 Although a-GalCer's ability to activate type I NKT cells is well studied by using splenic or liver NKT cells, there is limited information on NKT cells in tumor draining lymph nodes. In our study, the number of type I NKT cells in tumor draining lymph nodes was comparable to the frequency (0.1-0.2% of total lymph node cells) observed in na€ ıve lymph nodes.…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…CD80, CD83, CD86, CD83, CD40 and/or MHC Class II molecules), 166 (3) secretory activity, with specific reference to interleukin 1 beta (IL1B), IL6, IL12 and tumor necrosis factor (TNF), [167][168][169][170][171][172] and (4) T-cell crosspriming. [173][174][175][176][177][178][179][180][181] Of note, performing these ex vivo experiments with human cells generally involves allogeneic settings, since DCs or T cells derived from healthy individuals are typically not HLA-matched to human cancer cell lines. 156,[182][183][184][185][186][187][188][189][190] Thus, proper controls are needed for ruling out allogeneic graftversus-host immune reactions as confounding factors.…”

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.…”