Different routes of MHC-I delivery to phagosomes and their consequences to CD8 T cell immunity

Abstract

Dendritic cells (DCs) present internalized antigens to CD8 T cells through cross-presentation by major histocompatibility complex class I (MHC-I) molecules. While conventional cDC1 excel at cross-presentation, cDC2 can be licensed to cross-present during infection by signals from inflammatory receptors, most prominently Toll-like receptors (TLRs). At the core of the regulation of cross-presentation by TLRs is the control of subcellular MHC-I traffic. Within DCs, MHC-I are enriched within endosomal recycling compartments (ERC) and traffic to microbe-carrying phagosomes under the control of phagosome-compartmentalized TLR signals to favor CD8 T cell cross-priming to microbial antigens. Viral blockade of the transporter associated with antigen processing (TAP), known to inhibit the classic MHC-I presentation of cytoplasmic protein-derived peptides, depletes the ERC stores of MHC-I to simultaneously also block TLR-regulated cross-presentation. DCs counter this impairment in the two major pathways of MHC-I presentation to CD8 T cells by mobilizing noncanonical cross-presentation, which delivers MHC-I to phagosomes from a new location in the ER-Golgi intermediate compartment (ERGIC) where MHC-I abnormally accumulate upon TAP blockade. Noncanonical cross-presentation thus rescues MHC-I presentation and cross-primes TAP-independent CD8 T cells best-matched against target cells infected with immune evasive viruses. Because noncanonical cross-presentation relies on a phagosome delivery route of MHC-I that is not under TLR control, it risks potential cross-presentation of self-antigens during infection. Here I review these findings to illustrate how the subcellular route of MHC-I to phagosomes critically impacts the regulation of cross-presentation and the nature of the CD8 T cell response to infection and cancer. I highlight important and novel implications to CD8 T cell vaccines and immunotherapy.

Keywords: CD8 T cells; Cross-presentation; Dendritic cells; Noncanonical cross-presentation; Phagosomes; Toll-like receptors; Vesicular traffic.

Figure 1.. Subcellular localization and traffic of MHC-I molecules during TLR-regulated cross-presentation.

DC phagocytosis of microbes engages TLR-MyD88 signaling. A pathway of vesicular traffic is mobilized from MHC-I-rich ERC to TLR ligand (microbe)-carrying phagosomes. ERC-to-phagosome traffic is controlled by TLR-MyD88 signaling. Activation of IKK2 downstream of TLR-MyD88 signaling phosphorylates phagosomal SNAP-23 and stabilizes interactions of ERC R-SNAREs Endobrevin (VAMP8) and Cellubrevin (VAMP3) with phagosomal syntaxin 4 to mediate ERC-phagosome fusion. As a result, MHC-I molecules are delivered specifically to phagosomes carrying the microbial antigens which warrant cross-presentation during infection. This TLR-regulated pathway of cross-presentation favors the presentation of microbial antigens to CD8 T cells in the context of T cell costimulation during infection. Two other pathways of vesicular traffic emanating from the ERGIC and lysosome related organelles contribute additional components necessary for cross-presentation. See text for more details.

Figure 2.. Model for cross-priming CD8 T cells to immune evasive viruses through noncanonical cross-presentation.

A. It is widely believed that priming a CD8 T cell response against immune evasive viruses such as Herpesviridae and Poxviridae that block TAP, can only be achieved by uninfected DCs which acquire viral peptides from internalized infected dying cells and present them to T cells. This solution accommodates the paradigm that CD8 T cell immunity is impaired without TAP. However, the presentation of TAP-dependent peptides is severely reduced on tissues infected with immune evasive viruses or in cancers that downmodulate TAP, and instead those tissues or cancers present peptides independently of TAP. Thus, the MHC-I peptidome on these tissues or cancers presents either a diminished or a mismatched target for TAP-dependent CD8 T cells primed by TAP-sufficient DCs leading to inefficient CD8 T cell targeting of infected or cancer cells. B. Noncanonical cross-presentation intrinsic to DCs that have compromised TAP function enables the cross-presentation of epitopes generated in the absence of TAP function to CD8 T cells. The resultant TAP-independent CD8 T cell response is best matched for targeting TAP-independent epitopes presented by tissues infected with immune evasive viruses or in cancers that downmodulate TAP. Mobilization of noncanonical cross-presentation can thus have critical impact on the design of CD8 T cell vaccines to immune evasive viruses and successful immunotherapy for immune evasive cancers.

Figure 3.. Subcellular localization and traffic of MHC-I molecules during noncanonical cross-presentation of microbial or self antigens.

A. The ERC, which normally harbors large numbers of MHC-I molecules in DCs, becomes depleted of MHC-I molecules upon blockade of TAP. While TLRs continue to mobilize ERC-to-phagosome traffic, this traffic can no longer deliver MHC-I to phagosomes negatively impacting TLR-regulated cross-presentation. Under these conditions, DCs traffic MHC-I to phagosomes from the ERGIC instead of the ERC, in a manner dependent on the ER-SNARE protein Sec22b, to restore the MHC-I presentation of exogenously derived microbial peptides and rescue CD8 T cell priming. Because of the reliance on abnormal traffic of MHC-I, this pathway of antigen presentation is named as noncanonical cross-presentation. B. Noncanonical cross-presentation escapes regulation by TLR signals because it relies on trafficking MHC-I to phagosomes from the ERGIC, where they abnormally accumulate upon TAP blockade. Because TLRs do not control Sec22b-mediated traffic from the ERGIC to phagosomes, noncanonical cross-presentation carries the risk of cross-presenting peptides derived from phagocytosed apoptotic cells to self-reactive CD8 T cells in the context of infection-induced T cell costimulation.