By convention, presentation of major histocompatibility complex (MHC) class I-restricted epitopes involves processing by cytosolic proteasomes, whereas MHC class II-restricted epitopes are generated by endosomal proteases. Here, we show that two MHC class II-restricted epitopes within influenza virus were generated by a proteasome- and TAP-dependent pathway that was accessed by exogenous virus in dendritic cells (DCs) but not cell types with less permeable endosomes. Both epitopes were presented by recycling MHC class II molecules. Challenging mice with influenza or vaccinia viruses demonstrated that a substantial portion of the MHC class II-restricted response was directed against proteasome-dependent epitopes. By complementing endosomal activities, this pathway broadens the array of MHC class II-restricted epitopes available for CD4(+) T cell activation.
There is a high demand for the development of adjuvants that induce cytotoxic T lymphocytes, which are crucial for the elimination of intracellular pathogens and tumor cells. Toll-like receptor (TLR) agonists are prime candidates to fulfill this role because they induce innate immune activation and promote adaptive immune responses. The successful application of the TLR7 agonist R837 for treatment of basal cell carcinoma shows the potential for exploiting this pathway in tumor immunotherapy. Imidazoquinolines like R837 and stimulatory ssRNA oligonucleotides both trigger TLR7-mediated immune activation, but little is known about their comparative ability to promote immunity induction. We investigated differences in innate immune activation and adjuvant activity between the imidazoquinoline R848 and the ssRNA TLR7 agonist polyUs21. In contrast to R848, polyUs21 induced detectable levels of intracellular interferon-␣ (IFN-␣) in plasmacytoid dendritic cells (PDCs). In immunization studies, only polyUs21 led to robust priming of type 1 T helper cells and cytotoxic T lymphocytes, and it was more efficient in inducing antitumor immunity than R848. Notably, exogenous IFN-␣ augmented the adjuvant activity of R848, whereas depletion of PDC abrogated the adjuvanticity of polyUs21. This study, therefore, identifies sufficient IFN-␣ production by PDC as an important determinant of vaccine efficacy. (Blood. 2010;115:1949-1957 Introduction Cellular immune responses characterized by the induction of cytotoxic effector cells are crucial for therapeutic interventions in the context of tumor immunotherapy and for the induction of protective immunity against a variety of intracellular pathogens, such as the malaria parasite and HIV. A particular focus of novel vaccination strategies is the identification of adjuvants with the ability to skew adaptive immune responses toward a Th1 phenotype and thereby allow for the induction of cellular, in addition to humoral, immunity. 1 Synthetic mimics of pathogen-associated molecular patterns in general, and especially those mimicking virus presence, appear particularly potent in promoting the induction of cellular immunity and might therefore constitute powerful adjuvants. 2 Viral pathogen-associated molecular patterns can be detected by Toll-like receptors (TLRs) and cytoplasmic pattern recognition receptors. 3,4 The virus-sensing TLRs sample the contents of specialized endosomal compartments, where they detect bacterial and viral genomes, as well as viral replication intermediates. 3,4 Different classes of viral nucleic acids are detected by distinct TLRs with TLR3, TLR7/8, and TLR9 sensing dsRNA, ssRNA, and DNA, respectively. 3,4 Although various synthetic TLR agonists have been tried as adjuvants, 5 not many of them are approved for human use. In contrast, the TLR7/8 agonist R837 is approved for the topical treatment of genital warts, basal cell carcinoma, and bladder cancer. [6][7][8][9] Imidazoquinolines such as R837 and R848 originally were developed as small immune response modifiers ...
Antigen-presenting cells (APCs) are expected to present peptides from endocytosed proteins via major histocompatibility complex (MHC) class II (MHCII) molecules to T cells. However, a large proportion of peptides purified from MHCII molecules are derived from cytosolic self-proteins making the pathway of cytosolic peptide loading onto MHCII of critical relevance in the regulation of immune self-tolerance. We show that peptides derived from cytoplasmic proteins either introduced or expressed in the cytoplasm are first detectable as MHCII-peptide complexes in LAMP-1+ lysosomes, prior to their delivery to the cell surface. These peptide-MHC complexes are formed in a variety of APCs, including peritoneal macrophages, dendritic cells, and B cells, and are able to activate T cells. This process requires invariant chain (Ii)-dependent sorting of MHCII to the lysosome and the activity of the molecular chaperone H-2M. This pathway is independent of the ER resident peptide transporter complex TAP and does not take place by cross-presentation from neighbouring cells. In conjunction with our earlier results showing that these peptides are derived by cytosolic processing via the proteasome, these observations provide evidence for a ubiquitous route for peptide transport into the lysosome for the efficient presentation of endogenous and cytoplasmic proteins to CD4 T cells.
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