Antigen presentation and antigen presenting cell The basic

Antigen presentation and antigen presenting cell

The basic process of immune response Effector cells Antigen recognition Lymphocyte activation Memory cells

T cells do not recognize native antigens Antigen processing Recognize antigen that has been degraded into antigenic peptides and displayed with MHC molecules on the cell surface Antigen presentation T Y Y BCR B native antigenic peptide. MHC TCR antigen processing and presentation APC (antigen-presenting cell)

l CD 4 T cell recognize peptide associated with MHC class II molecules l CD 8 T cell recognize peptide associated with MHC class I molecules

Class I MHC molecule Class II MHC molecule What determines whether an antigenic peptide associates with class I or with class II molecules?

l It is dictated by the mode of entry into the cell, either exogenous or endogenous. p Class I MHC molecules bind peptides derived from endogenous antigens p Class II MHC molecules bind peptides derived from exogenous antigens

Exogenous antigen -is produced outside of the host cell enter the cell by endocytosis or phagocytosis

Endogenous antigen -is produced within the host cell itself Øviral proteins Øtumor proteins

Two processing and presentation pathways p. Endogenous antigens l l processed in the cytosolic pathway presented with class I MHC molecules p Exogenous antigens l l processed in the endocytic pathway presented with class II MHC molecules

Endogenous antigens: the cytosolic pathway Intracellular proteins are degraded into short peptides by a proteasome (a cylindrical particle with a central channel) Degradation of protein occur within the central hollow of the proteasome

Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I Endoplasmic reticulum (ER) Newly synthesised MHC class I molecules Cytosol Peptides need access to the ER in order to be loaded onto MHC class I molecules

Transporters associated with antigen processing (TAP 1 & 2) peptides are translocated by TAP into the ER Hydrophobic transmembrane domain Lumen of ER Peptide ER membrane Cytosol TTA --22 AP P TA AAP P--1 -1 1 AP P-2 TT T Peptide antigens from proteasome ATP-binding cassette (ABC) domain TAP is optimized to transport peptides that will interact with class I MHC

Peptides assemble with class I MHC aided by chaperone molecules Peptide TA P- P 1 -1 1 AP TATAP- AP P-2 T 2 2 Peptide Endoplasmic reticulum B 2 -M Calnexin binds and to nascent stabilises class I chain floppy until 2 -M binds MHC Tapasin, calreticulin, TAP Peptides are loaded form a complex with the onto the MHC molecule floppy MHC and the structure becomes compact

Fate of MHC class I Exported to the cell surface Sent to lysosomes for degradation

Endogenous antigens: the cytosolic pathway Cell surface Golgi ER calnexin Cytoplasm peptide Endogenous antigen

Exogenous antigens: the endocytic pathway Cell surface Uptake degraded into peptides Endosomes Increase in acidity proteases are activated by the decrease in p. H Proteases produce 13~18 amino acid long peptides from antigens

MHC class II maturation and invariant chain In the endoplasmic reticulum prevent any endogenously derived peptides from binding to class II molecules invariant chain (Ii chain) interacts with the peptide-binding cleft of the class II molecules

MHC class II compartment (M II C) Cell surface Uptake Ii complex exit from the ER Endosomes a short fragment of the Ii chain termed class II associated invariant chain peptide (CLIP) occupies the peptide-binding groove

Removal of CLIP ? How can the peptide bind to the peptide-binding groove of class II molecules?

HLA-DM is required to catalyze the exchange of CLIP with antigenic peptides HLA-DM M II C

Surface expression of MHC class II-peptide complexes Transported to the cell surface Sent to lysosomes for degradation

Exogenous antigens: the endocytic pathway

p. Which cells can present antigen to CD 8+ T cells? And Why? l All nucleated cells p. Which cells can present antigen to CD 4+ T Cells? And Why? l Professional antigen presenting cells Dendritic Cells Macrophages B cells

Antigen presenting cell (APC) Professional APCs are distinguished by two properties: pexpress class II MHC molecules on their membranes pdeliver a co-stimulatory signal that is necessary for CD 4 T cell activation Nonprofessional APCs: pbe induced to express class II MHC molecules or a costimulatory signal p function in antigen presentation only for short periods of time during a sustained inflammatory response

Classification of APC

p Dendritic cells are the most effective of APCs l constitutively express a high level of class II MHC molecules and costimulatory activity l activate naive CD 4 T cells p Macrophages must be activated before they express class II MHC molecules or the costimulatory molecules p B cells constitutively express class II MHC molecules but must be activated before they express the co-stimulatory molecules

Dendritic cell (DC) pacquire their name because of the numerous long membrane extension similar to the dendrites of neurons

Immature vs. Mature DCs Immature DCs express TLR, Fcg. R, C 3 b. R, and class I and II MHC I/II molecules. They are good at antigen uptaking and processing, but poor at inducing T cell activation. Mature DCs are derived from immature DCs upon stimulation by TLR signals and various cytokines, expressing high levels of co-stimulatory molecules. While losing antigen capturing capacity, they are stronger inducers of T activation.

Name by Tissue Distribution DCs in non-lymphoid tissues Interstitial DC Identified in all tissues other than the brain Langerhans Cell Found in the epidermal layers of the skin Both are particularly good at antigen capturing

Name by Tissue Distribution DCs in lymphoid tissues Interdigitating DC （IDC） Mainly found in T cell area in lymphoid tissues Expressing high levels of class II MHC and co-stimulatory molecules Particularly potent in T cell activation Follicular DC (FDC) Mainly found in lymphoid follicules Expressing high levels of Fc receptor and complement receptor Critical in germinal center reaction do not function as antigen presenting cells

What to remember The two major pathways for antigen presentation The features of three major types of professional APCs

Study question l l l Define the following terms: Exogenous antigen -is produced outside of the host cell Endogenous antigen -is produced within the host cell itself

Study question l l l CD 4 Th cells recognize antigen with class (II) MHC molecules on (antigen-processing) cells. CD 8 TC cells recognize antigen with class (I) MHC molecules on (target) cells. (Endogenous) antigens are degraded into peptides within the cytosol by (proteasomes) and assemble with class (I) molecules in the RER.

Study question l l Cells that can present antigen to TH cells have been classified into two groups— (professional) and (nonprofessional) APCs. (Dendritic cells) are the most effective of APCs

Study question Fill in the blanks in the following statements with the most appropriate terms: a. ( ), ( ) and ( ) all function as professional antigen presenting cells. b. Only antigen-presenting cells express class ( ) MHC molecules, whereas nearly all cells express class ( ) MHC molecules. c. ( ) antigens are internalized by antigen-presenting cells, degraded in the ( ), and displayed with class ( ) MHC molecules on the cell surface. d. ( ) antigens are produced in altered self-cells, degraded in the ( ), and displayed with class ( ) MHC molecules on the cell surface. l