In vitro and in vivo processing studies of peptide antigens in context of MHC class II presentation (original) (raw)
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The ins and outs of MHC class II-mediated antigen processing and presentation
MHC class II-restricted antigen presentation is essential for CD4 + T cell-dependent immune responses. Different professional antigen-presenting cells (APCs) participate in a wide range of processes that are necessary for the generation of an effective and specific immune response. Dendritic cells (DCs) sample their environment and capture foreign antigens, such as those derived from bacteria or viruses, and initiate adaptive immune responses against these antigens by activating CD4 + and CD8 + T cells 1 . DCs and epithelial cells in the thymus express (and also capture) numerous self proteins and contribute to central tolerance and peripheral tolerance. By contrast, each B cell generally captures a single antigen after binding to its antigen-specific surface B cell receptor (BCR) 2 and then presents peptides from this antigen to specific T cells. Regardless of APC type, all APCs specifically interact with distinct subsets of T cells that express antigen-specific T cell receptors (TCRs) on their surface. The specificity of this interaction depends on the ability of APCs to display antigenic peptides, immobilized by MHC class I and class II molecules, on their surface. MHC class II binds antigenic peptides that are generated by proteolysis of self and non-self proteins in endosomes and lysosomes, and 'presents' them to antigen-specific CD4 + T cells 3 . Recognition of peptide-MHC class II by CD4 + T cells stimulates their activation and differentiation into T helper cell subsets Abstract | Antigenic peptide-loaded MHC class II molecules (peptide-MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4 + T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide-MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide-MHC class II complexes, the intracellular trafficking of peptide-MHC class II complexes to the APC plasma membrane and their ultimate degradation.
2013
It is generally assumed that the MHC class I antigen (Ag)-processing (CAP) machinery-which supplies peptides for presentation by class I molecules-plays no role in class II-restricted presentation of cytoplasmic Ags. In striking contrast to this assumption, we previously reported that proteasome inhibition or TAP-or ERAAP-deficiency led to dramatically altered T helper (Th) cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags. Herein, we tested whether altered Ag processing and presentation, altered CD4 + T cell repertoire, or both underlay the above finding. We found that TAP-and ERAAP-deficiency dramatically altered the quality of class II-associated self peptides suggesting that the CAP machinery impacts class II-restricted Ag processing and presentation. Consistent with altered self peptidomes, the CD4 + T cell receptor repertoire of mice deficient in the CAP machinery substantially differed from that of wildtype animals resulting in altered CD4 + T cell Ag recognition patterns. These data suggest that TAP and ERAAP sculpt the class II-restricted peptidome, impacting the CD4 + T cell repertoire, and ultimately altering Th cell responses. Together with our previous findings, these data suggest multiple CAP machinery components sequester or degrade MHC class II-restricted epitopes that would otherwise be capable of eliciting functional Th cell responses.
The Journal of Immunology
Class I1 MHC molecules on the surface of an APC present immunogenic peptides derived mainly from exogenous proteins to CD4+ T cells. During its transport to the cell surface, class XI molecules intersect the endocytic pathway where they acquire peptides derived from endocytosed proteins. However, class 11-restricted presentation of endogenously derived peptides can also occur. The current studies were undertaken to examine the ability of different types of APC to generate and present four different T cell determinants derived from an endogenous, nonsecreted, truncated form of hen-egg white lysozyme (HEL[1-80]-Kk). This was compared with the ability of these APC to generate the same determinants from exogenous HEL. All the peptides derived from endogenous HEL[ 1-801-Kk tested, were presented by B cells to HEL-specific T cell hybridomas with an efficiency similar to presentation of the same determinants from exogenous HEL. In contrast, an 1-A"bearing rat fibroblast was unable to generate the HEL peptide 25-43 from exogenous HEL, but could efficiently produce it from endogenous HEL[ 1-801-K". The results indicate first, that peptides derived from an endogenous Ag can be presented by MHC class I1 molecules with an efficiency comparable to that of the presentation of the exogenous Ag. Second, that Ag-presenting B cells can generate the same repertoire of antigenic peptides from endogenous Ag as those generated from the exogenous protein. And third, that in contrast to B cells, certain "nonprofessional" APC can generate, from an endogenous protein, T cell determinants distinct from those generated after endocytosis of the exogenous protein. These results suggest that processing of exogenous and endogenous Ag by different APC take place in different intracellular compartments. Unlike Ig, the TCR recognizes protein Ag a s peptides associated to MHC molecules on the surface of an APC (1). The MHC class I molecules generally bind and present peptides derived from proteins synthesized within the
Immunology, 2012
An understanding of factors controlling CD4 T-cell immunodominance is needed to pursue CD4 T-cell epitope-driven vaccine design, yet our understanding of this in humans is limited by the complexity of potential MHC class II molecule expression. In the studies described here, we took advantage of genetically restricted, well-defined mouse strains to better understand the effect of increasing MHC class II molecule diversity on the CD4 T-cell repertoire and the resulting anti-influenza immunodominance hierarchy. Interferon-c ELISPOT assays were implemented to directly quantify CD4 T-cell responses to I-A b and I-A s restricted peptide epitopes following primary influenza virus infection in parental and F 1 hybrid strains. We found striking and asymmetric declines in the magnitude of many peptide-specific responses in F 1 animals. These declines could not be accounted for by the lower surface density of MHC class II on the cell or by antigen-presenting cells failing to stimulate T cells with lower avidity T-cell receptors. Given the large diversity of MHC class II expressed in humans, these findings have important implications for the rational design of peptide-based vaccines that are based on the premise that CD4 T-cell epitope specificity can be predicted by a simple cataloguing of an individual's MHC class II genotype.
Presentation of Cytosolic Antigens Via MHC Class II Molecules
Immunologic Research, 2004
Major histocompatibility (MHC) class II molecules function to present antigenic peptides to CD4 T lymphocytes. The pathways by which these molecules present exogenous antigens have been extensively studied. However by contrast, far less is known about the processing and trafficking of cytosolic antigens, which can also serve as an alternative source of ligands for MHC class II molecules. Self-proteins, tumor antigens, as well as viral proteins found within the cytosol of cells, can be presented via MHC class II molecules, resulting in the activation of specific CD4 T cells. Studies have begun to reveal unique steps as well as some similarities in the pathways for cytosolic and exogenous antigen presentation. Recent developments in this area are summarized here.
The Journal of Immunology
Immune responses mediated by CD4+ T cells depend on Ag-specific alpha beta TCRs that recognize the specific antigenic peptide presented by MHC class II molecules. Interactions between CD4 coreceptors and monomorphic regions of MHC class II molecules contribute to these responses. To examine whether immune reactions could be modulated by specifically interfering with CD4-MHC class II interactions, we have used, in various in vitro and in vivo assays, peptides that correspond to a region of MHC class II molecules previously shown to control interaction with CD4. Depending on the chemical nature and concentration of these peptides, they modulated Ag-specific responses of CD4+ T cells. At high concentrations, these peptides inhibited T cell responses in vitro. However, under conditions that can cause Ag-induced unresponsiveness, the peptides enhanced T cell responses. Also, primary in vivo immune responses to systemically administered soluble protein Ag, keyhole limpet hemocyanin, were ...