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The function of intracellular trafficking in immune-complex triggered inflammation remains poorly understood. Here, we investigated the role of Insulin-Regulated Amino Peptidase (IRAP)-positive endosomal compartments in Fc receptor (FcR)-induced inflammation. Less severe FcγR-triggered arthritis, active systemic anaphylaxis and FcεRI-triggered passive systemic anaphylaxis were observed in IRAP-deficient versus wild-type mice. In mast cells FcεRI stimulation induced rapid plasma membrane recruitment of IRAP-positive endosomes. IRAP-deficient cells exhibited reduced secretory responses, calcium signaling and activating Syk Y519/520 phosphorylation albeit receptor tyrosine phosphorylation on β and γ subunits was not different. By contrast, in the absence of IRAP, SHP1-inactivating phosphorylation on Ser 591 that controls Syk activity was decreased. Ex-vivo cell profiling after FcγR-triggered anaphylaxis confirmed decreased phosphorylation of both Syk Y519/520 and SHP-1 S591 in IRAP-deficient neutrophils and monocytes. Thus, IRAP-positive endosomal compartments, in promoting inhibition of SHP-1 during FcR signaling, control the extent of phosphorylation events at the plasma membrane and contribute to setting the intensity of immune-complex triggered inflammatory diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bratti, Vibhushan, Longé, Koumantou, Ménasché, Benhamou, Varin-Blank, Blank, Saveanu and Ben Mkaddem.)

Phosphoinositide-3 kinases (PI3Ks) generate 3-phosphorylated phosphoinositide lipids that are implicated in many biological processes in homeostatic states and pathologies such as cancer, inflammation and autoimmunity. Eight isoforms of PI3K exist in mammals and among them the class I PI3K, p110γ, and PI3Kδ, and class III Vps34 being the most expressed and well characterized in immune cells. Following engagement of pathogen recognition receptors (PRRs), PI3Ks coordinate vital cellular processes of signaling and vesicular trafficking in innate phagocytes such as macrophages and professional antigen presenting dendritic cells (DCs). Although previous studies demonstrated the involvement of PI3K isoforms in innate and adaptive immune cell types, the role of PI3Ks with respect to DC biology has been enigmatic. Thus, this review, based on studies involving PI3K isoforms, highlight how the different PI3Ks isoforms could regulate DC functions such as antigen processing and presentation including PRR responses.

Dendritic cells (DCs) have the unique ability to pick up dead cells carrying antigens in tissue and migrate to the lymph nodes where they can cross-present cell-associated antigens by MHC class I to CD8(+) T cells. There is strong in vivo evidence that the mouse XCR1(+) DCs subset acts as a key player in this process. The intracellular processes underlying cross-presentation remain controversial and several pathways have been proposed. Indeed, a wide number of studies have addressed the cellular process of cross-presentation in vitro using a variety of sources of antigen and antigen-presenting cells. Here, we review the in vivo and in vitro evidence supporting the current mechanistic models and disscuss their physiological relevance to the cross-presentation of cell-associated antigens by DCs subsets.

Cross-presentation, in which exogenous antigens are presented via MHC I complexes, is involved both in the generation of anti-infectious and anti-tumoral cytotoxic CD8(+) T cells and in the maintenance of immune tolerance. While cross-presentation was described almost four decades ago and while it is now established that some dendritic cell (DC) subsets are better than others in processing and cross-presenting internalized antigens, the involved molecular mechanisms remain only partially understood. Some of the least explored molecular mechanisms in cross-presentation concern the origin of cross-presenting MHC I molecules and the cellular compartments where antigenic peptide loading occurs. This review focuses on MHC I molecules and their intracellular trafficking. We discuss the source of cross-presenting MHC I in DCs as well as the role of the endocytic pathway in their recycling from the cell surface. Next, we describe the importance of the TAP peptide transporter for delivering peptides to MHC I during cross-presentation. Finally, we highlight the impact of innate immunity mechanisms on specific antigen cross-presentation mechanisms in which TLR activation modulates MHC I trafficking and TAP localization.

Production of MHC-I ligands from antigenic proteins generally requires multiple proteolytic events. While the proteolytic steps required for antigen processing in the endogenous pathway are clearly established, persisting gaps of knowledge regarding putative cross-presentation compartments have made it difficult to map the precise proteolytic events required for generation of cross-presented antigens. It is only in the past decade that the importance of aminoterminal trimming as the final step in the endogenous presentation pathway has been recognized and that the corresponding enzymes have been described. This review focuses on the aminoterminal trimming of exogenous cross-presented peptides, with particular emphasis on the identification of insulin responsive aminopeptidase (IRAP) as the principal trimming aminopeptidase in endosomes and phagosomes.