Module 3

MHC

Differentiate self from non-self
Display antigenic peptides on cell surface
Recognized by TCR and CD4/CD8
Initiate adaptive response

MHC Classification

Distinguish recognition patterns
Class 1 and 2

APC

Recognize and present extracellular pathogens to helper T-cells
Display peptides on MHC class 2 complexes

APC: Receptor-Mediated Endocytosis

Endocytosis relying on specific receptors
Process pathogens into peptides

APC: Professional

Efficient
MHC class 2 antigen presentation
Express co-stimulatory signals
Activate helper T-cells
Ex: Macrophage, B-cell, dendritic cell

APC: Non-Professional

Induce MHC class 2 and stimulatory molecule expression
Ex: Fibroblasts, glial cells

Adaptive 1: Antigen Recognition

APC recognize PAMPs
Present antigen in MHC complex to naïve T-cells
T-cell activation

Adaptive 2: Lymphocyte Activation

T- and B- cell differentiation
Clonal expansion
B-Cells: Plasmocytes
T-Cells: Helper T-cells, cytotoxic T-cells

Adaptive 3: Pathogen Elimination

Release defences
Destroy pathogen
Humoral Immunity: Plasmocytes produce antibodies binding extracellular pathogens
Cell-Mediated Immunity: Cytotoxic T-cells destroy intracellular pathogens

Adaptive 4: Contraction

Activated lymphocytes undergo apoptosis
Immune response decreases

Adaptive 5: Immunological Memory

Immune cells differentiate into memory cells
Faster and stronger immune response upon re-exposure

Cytokines: Chemokines

Induce chemotaxis
Recruit immune cells to high chemoattractant molecule concentration areas
Inflammation and wound healing
Cell-mediated and humoral responses
Hematopoiesis

Cytokines: Interleukins

Immune and inflammatory responses
Affect hematopoietic and immune cell proliferation and differentiation

Cytokines: Interferons

Induce antiviral state
Inhibit virus replication
Regulate immune responses

Cytokines: Tumour Necrosis Factor

Cause apoptosis
Systemic inflammation (septic shock)
Tumor regression

Cytokines: Growth Factors

Stimulate growth, proliferation, healing, cell differentiation
Regulate cellular and immune processes

Antigen Processing

Forming effective peptide:MHC signalling complexes

Endogenous Antigen Processing

Form peptide:MHC class 1 complex
For CD8+ cytotoxic T-cells

Exogenous Antigen Processing

Form peptide:MHC class 2 complex
For CD4+ helper T-cells

Endogenous Antigen Processing 1: Processing

Intracellular self and foreign particles
Degrade into peptide fragments
Associate with MHC class 1 in ER

Endogenous Antigen Processing 2: MHC Class 1 Processing

In Golgi
Form peptide:MHC class 1 complex

Endogenous Antigen Processing 3: Presentation

Present MHC class 1 on cell surface
Recognize by T-cell receptors on cytotoxic T-cells

Exogenous Antigen Processing 1: Antigen Engulfment

APC endocytose foreign antigen
Form endosome
PRR recognize antigen

Exogenous Antigen Processing 2: Proteolytic Processing

Protease cleave protein
Modify activity
Endosome break down foreign antigen

Exogenous Antigen Processing 3: MHC-Antigen Complex

Vesicles from ER via Golgi
Fuse foreign fragments and MHC molecules
Form MHC-antigen complexes

Exogenous Antigen Processing 4: Cell Surface Expression

Transport MHC-antigen complex to plasma membrane
Display on cell surface

Exogenous Antigen Processing 5: Helper T-Cell

Helper T-cell receptor bind MHC-antigen complex
Initiate adaptive response

B-Cell Receptor

Membrane-bound antibody + signal transduction molecules (ITAMs)
Repeated 4 amino acids in cytoplasmic tails of cell surface proteins
Recognize and bind extracellular pathogen

ITAM

Immunoreceptor tyrosine-based activation motif

T-Cell Receptor

Membrane-bound antigen-specific molecule + signal transduction molecules (CD3 and ITAMs)
Recognize and bind peptide:MHC complex
CD4: MHC class 2
CD8: MHC class 1

Cross-Presentation: Exogenous Pathogens

To CD8 T-cells after CD4 presentation
Load on MHC class 1

Cross-Presentation: Endogenous Pathogens

To CD4 T-cells after CD8 presentation
Load on MHC class 2

Immune System Communication

Coordinate effective immune response

Communication: Lymphocyte Activation

Immune response efficiency

Communication: Cytokine Network

Balance humoral and cell-mediated immunity

B-Cell Activation by T-Cell

CD4+ helper T-cells stimulate humoral immunity
Exchange activation signals

B-Cell Activation: Thymus-Dependent Antigens

Induce antibody production with T-cell

B-Cell Activation: Thymus-Independent Antigens

Induce antibody production without T-cell

B-Cell Activation 1: MHC Class 2 Complex

Antigen bind B-cell receptor
Receptor-mediated endocytosis of antigen
Process and display antigen on MHC complex
B-cell act as APC

B-Cell Activation 2: Signal 1

Specific T-cell receptor complex and CD4 binds peptide:MHC class 2 complex

B-Cell Activation 3: Co-Stimulatory Molecule Expression

Signal 1 induce CD40L expression on helper T-cell surface

B-Cell Activation 4: Signal 2

CD40L and CD28 on T-cells bind CD40 and B7 on B-cells
Induce costimulatory signals

B-Cell Activation 5: Signal 3

Activated helper T-cell secrete cytokines
Bind cytokine receptor on T- and B- cells
Paracrine and autocrine effect

B-Cell Activation 6: Outcome

Signals stimulate B-cell differentiation
Initiate humoral immunity

Immune Synapse

Interaction between T-cell and APC
For proper T-cell activation

Immune Synapse: Bullseye

3 rings of cell clusters (SMAC)

SMAC

Supra molecular activating clusters

cSMAC

Signal molecules
Central SMAC
Intercell signalling
Strong adhesive properties
Ex: TCR, peptide:MHC molecules

pSMAC

Adhesion molecules
Peripheral SMAC
Maintain contact for signal propagation
Ex: Integrins, cytoskeletal linker proteins

dSMAC

Signal regulation molecules
Distal SMAC
Proteins with large extracellular domains
Regulate signal transduction

Immune Synapse Functions

Effective T-cell activation
Hold signal proteins together for stronger connection and signal propagation
Reorganize T-cell structures
Direct cytokine release to target cell
Regulate lymphocyte activation

Incomplete Synapse Activation

Incomplete T-cell activation and proliferation
Decrease immune response
Non-functional (anergic) cell development

Immunological Memory

Lymphocyte respond more efficiently to re-infection by previously encountered antigen

Memory B-Cells

B-cell mediated reduction of immune reactivity

Memory B-Cell Differentiation

From naïve B-cells
Same membrane-bound antibody
APC activated

Memory B-Cell Differentiation: Plasmocytes

Immediately from memory B-cells
Fast immune response
No costimulatory molecule

Memory B-Cell: Life Span

Lifelong immunity

Natural Passive Immunity

Mother to fetus
Placental antibody transfer
Temporary (6 months)
No immunological memory

Artificial Passive Immunity

Antibody serum injection
Temporary
No immunological memory

Natural Active Immunity

Pathogen infection
Symptoms/disease state
Develop innate and adaptive responses
Probable immunological memory

Artificial Active Immunity

Vaccination
No symptoms/disease state
Develop innate and adaptive responses
Immunological memory