Lez 15 (3 del modulo 3) Homing and trafficking of DC during their maturation CCR7-/CCR5+ CCR7+/CCR5- Molecules expressed by matured DC ADATTATIVA : recettori distribuiti clonalmente Riarrangiamento Genico Precursore Antigene Clone ADATTATIVA : recettori distribuiti clonalmente Riarrangiamento Genico Precursore Antigene Clone Encounter with THE antigen generates effector T cells and long-lived memory T cells. The central role of CD4+ T lymphocytes Different types of antigen-presenting cells La restrizione MHC (Major Histocompatibility Antigen) I linfociti T “vedono” l’antigene solo se presentato all’interno di MHC “self” Vaccini con DC autologhe I linfociti vengono attivati soltanto dal riconoscimento di un antigene estraneo NON-SELF A 1° segnale TCR LINFOCITA T A A Ag MHC Cellula che presenta B B Menu F B Menu F B Menu F The MHC molecules of an individual do not discriminate between foreign peptides (e.g., those derived from microbial proteins) and peptides derived from the proteins of that individual (self antigens ). The binding of peptides to MHC molecules is a noncovalent interaction mediated by residues both in the peptides and in the clefts of the MHC molecules. The antigen receptors of T cells recognize both the antigenic peptide and the MHC molecules, with the peptide being responsible for the fine specificity of antigen recognition and the MHC residues accounting for the MHC restriction of the T cells. 8-11 residues Antigen competition for T cells. A T cell recognizes a peptide presented by one MHC molecule. An excess of a different peptide that binds to the same MHC molecule competitively inhibits presentation of the peptide that the T cell recognizes. APC, antigen-presenting cell. T cell recognition of a peptide-MHC complex. This schematic illustration shows an MHC molecule binding and displaying a peptide and a T cell receptor recognizing two polymorphic residues of the MHC molecule and one residue of the peptide. Non MHC ristretto MHC genes control graft rejection and immune responses. The two strains of mice shown are identical except for their MHC alleles (referred to as a and b). These strains reject skin grafts from each other (A) and respond differently to immunization with a model protein antigen (usually a simple polypeptide) (B). HLA: human leukocyte antigen (chromosom 6) B Menu F Lez 16 (4 del modulo 3) Protein antigens present in acidic vesicular compartments of APCs generate class II-associated peptides, whereas antigens present in the cytosol generate class Iassociated peptides. Pathways of antigen processing and presentation. In the class II MHC pathway (top panel), extracellular protein antigens are endocytosed into vesicles, where the antigens are processed and the peptides bind to class II MHC molecules. In the class I MHC pathway (bottom panel), protein antigens in the cytosol are processed by proteasomes, and peptides are transported into the ER, where they bind to class I MHC molecules. Comparative Features of Class II and Class I MHC Pathways of Antigen Processing and Presentation Feature Class II MHC Pathway Class I MHC pathway Composition of stable peptideMHC complex Polymorphic α and β chains, Polymorphic α chain, β2-microglobulin, Types of APCs Dendritic cells, mononuclear phagocytes, B lymphocytes; endothelial cells, thymic epithelium All nucleated cells Responsive T cells CD4+ T cells CD8+ T cells Source of protein antigens Endosomal/lysosomal proteins (mostly internalized from extracellular environment) Cytosolic proteins (mostly synthesized in the cell; may enter cytosol from phagosomes) Enzymes responsible for peptide generation Endosomal and lysosomal proteases (e.g., cathepsins) Cytosolic proteasome Site of peptide loading of MHC Specialized vesicular compartment Endoplasmic reticulum Molecules involved in transport of peptides and loading of MHC molecules Chaperones in ER; invariant chain in ER, Golgi and MIIC/CIIV; DM Chaperones, TAP in ER Abbreviations: APC, antigen-presenting cell; CIIV, class II vesicle; ER, endoplasmic reticulum; MHC, major histocompatibility complex; MIIC, MHC class II compartment; TAP, transporter associated with antigen processing Class II MHC Class I MHC Pathophysiological significance of Class I-associated antigen presentation Riconoscere l’antigene con il TCR specifico non basta! E’ necessario un 2° segnale dato dalla cellula che presenta l’antigene IMPORTANCE OF CO-STIMULATION 1° segnale 2° segnale B B Menu B Menu I tumori sperimentali murini esprimono antigeni immunogenici Prehn 1950 Mechanisms of evasion from immune surveillance •Tumor antigens are poorly immunogenic •Lack or loss of immunogenic peptides •Loss of MHC molecules •Lack of co-stimulatory molecules •Production of immune-suppressive factors (IL-10, TGFb, VEGF ……) •Low frequency of tumor specific effectors •Alteration of effector mechanisms •Activation of suppressor T cells
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