Control of dendritic cell cross-presentation by the major histocompatibility complex class I cytoplasmic domain

Abstract

Dendritic cells (DCs) can present extracellularly derived antigens in the context of major histocompatibility complex (MHC) class I molecules, a process called cross-presentation. Although recognized to be important for priming of T cell responses to many viral, bacterial and tumor antigens, the mechanistic details of this alternative antigen-presentation pathway are poorly understood. We demonstrate here the existence of an endolysosomal compartment in DCs where exogenously derived peptides can be acquired for presentation to T cells, and show that the MHC class I cytoplasmic domain contains a tyrosine-based targeting signal required for routing MHC class I molecules through these compartments. We also report that transgenic mice expressing H-2K(b) with a tyrosine mutation mount inferior H-2K(b)-restricted cytotoxic T lymphocyte responses against two immunodominant viral epitopes, providing evidence of a crucial function for cross-priming in antiviral immunity.

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

“…This is supported by in vitro safety analyses, which demonstrated that rozanolixizumab showed no effect on cytokine production. Although the FcRn C-terminal (intracellular) domain contains motifs that may be associated with endocytosis and trafficking, 57,58 it lacks the immunoreceptor tyrosine-based activation motif (ITAM) and immunoreceptor tyrosine-based inhibition motif (ITIM) that are associated with the transmembrane signalling observed with other Fc receptors. 59 Although Baker et al 60 reported that in dendritic cells, interaction between FcRn and immune complexes can lead to secretion of IL-12, to our knowledge there is no mention in the literature of cellular signalling that occurs as a result of FcRn binding its natural ligands, IgG or albumin.…”

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

“…The reason for this discrepancy is unclear but might be related to the differentiation state of the iDC, as their cells were isolated at a somewhat earlier time point as compared to our iDC. Lizée et al [10] recently demonstrated that MHC class I molecules are targeted to an endolysosomal compartment for loading of exogenously derived peptides through a tyrosine-based targeting signal in the cytoplasmic domain. Interestingly, they also found that transgenic mice expressing a mutant form of H2-K b lacking tyrosine in this position mounted reduced CTL responses to two immunodominant viral epitopes, and DC from these mice did not process and present OVA in vitro.…”

“…The endolysosomal compartment can obtain MHC class I molecules either directly from the ER or by recycling from the cell surface [9,11] and can export, by regurgitation, antigenic material for the direct binding to MHC class I expressed on the cell surface [12]. The leakage pathway is unique to DC, whereas the endolysosomal pathway has been mostly described for other cells, including B cells, macrophages and neutrophils [5-9, 11, 12] but was also recently reported for DC [10,13,14]. It is presently not clear if MHC class Ibinding peptides are formed in endolysosomes or if phagosomes are also involved in this process.…”

“…where this could occur have been suggested: transfer from uptake vesicles into the cytosol followed by the classical MHC class I pathway [5] and processing and peptide loading of MHC class I in endolysosomes or phagosomes [6][7][8][9][10]. The endolysosomal compartment can obtain MHC class I molecules either directly from the ER or by recycling from the cell surface [9,11] and can export, by regurgitation, antigenic material for the direct binding to MHC class I expressed on the cell surface [12].…”

“…It has been suggested that antigens are first cleaved into larger fragments, which then are exported into the cytosol for further processing into peptides by the proteasomal complex. Peptides could then reenter phagosomes, as these express TAP, bind to MHC class I and eventually be expressed as peptide/MHC class I complexes on the cell surface [10]. The classical MHC class I processing pathway can be distinguished from a fully independent endolysosomal pathway in experiments using TAP -/-cells or drugs that prevent proteolysis in proteasomes or the transport of peptide/MHC class I complexes through the Golgi system [lactacystin and Brefeldin A (BFA), respectively].…”