Cell-Mediated Immunity Flashcards
How do Macrophages use Co-stimulatory signals
- Macrophage phagocytized bacteria and break them down
- Induces expression of MHC class II and B7
- T-Cell recognizes the MHC Class II and the antigen presented
- T-Cell recognizes the co-stimulatory B7 signal through CD28 receptors
- Proliferation and differentiation of T-Cells specific for bacterial protein
MHC Class II
- Where are they found
- What do they form complexes with
- What receptors do they present their antigens to
Found in antigen presenting cells
Forms complex with exogenous antigens
Presents antigens to T-Helper Lymphocytes (CD4)
What are the different methods of CD8 T-Cell Activation
Autocrine
- Dendritic cells express high amounts of B7 which is recognized by CD28 receptors
- Dendritic cells presents antigen:MHC which is recognized by TCR
- T-cell is activated and releases its own IL-2 driving its own proliferation and differentiation
Co-Stimulatory
- Adjacent CD4 T-Cell is activated by APC
- Which in turn activates APC causing it to secrete B7
- CD8 is then activated, IL-2 is produced
Paracrine
- APC activates CD4 T-Cell, causing it to secrete IL-2
- IL-2 then activates IL-2 receptors on the CD8 T cell
What is B7
Once activated APCs express B7, the B7 ligand then riggers CD28 receptors on T-Cells
What is the function of a Helper T-Cell
- T1 Helper Cell: Activates Macrophages using cytokines
- T2 Helper Cell: Uses cytokines to activate B-Cells so that they differentiate into plasma cells and secrete antibodies
Which Human MHC Class I and Class I Isotypes are monomorphic
Class I
- F
- Beta 2 Microglobulin
Class II
- DO
MHC Class II
- Processing and Presentation process of antigens
- Extracellular material is taken in through endocytosis and phagocytosis (By phagosomes)
- This material is then taken into the vesicular system of the cell (Ex. Macrophages)
- When the phagosome fuses with a lysosome the proteases and hydrolases break down the proteins to produce peptides
- MHC class II are transported into these vesicles through the ER and Golgi apparatus
- These peptides are then bound to MHC class II
- The Peptide:MHC Class II complex is then transported to the cell’s surface through outgoing vesicles
- MHC class II presents peptide at cell surface
What is the CD3 Complex
- What polypeptides make up the complex
Facilitates signaling for the T-Cell Receptor
- Gamma
- Delta
- Epsilon
- Zeta
What happens when T-Cell is activated
- T-Cell synthesizes and secretes IL-2 (For autocrine and/or paracrine action)
- This induces T-cell proliferation and differentiation
How many MHC Class I Isotypes are there?
- What are they?
6 Isotypes
HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G
What kind of MHC do Kidney cells express
Express some Class I
What is the function of a Cytotoxic T-Cell
Will kill host cells infected by virus
What response does a T-Cell give if it recognizes the antigen but not co-stimulation
Anergy
- A non-responsive state
Helps protect against T-cells recognizing the body’s own tissue
What is the Antigen Processing and Presenting Process
- Ag processing:
- Proteins are degraded into peptides - Host cells then sample these peptides
- Host cells then assemble a MHC:Peptide complex
- Ag Presenting:
- The MHC:Peptide Complex is the presented on the surface of the host cell
What kind of MHC do Hepatocytes express
Express some Class I
What are the 8 polypeptides that make up the whole T-Cell Receptor Complex
- Alpha and Beta make up the main body
- 2 Zeta on the bottom
- Delta and Epsilon on the left
- Gamma and Epsilon on the right
Which Human MHC Class I and Class I Isotypes are Polymorphic
Class II
- DP, DQ
Helper T-Cell Activation
APCs activating CD4 TH1-Cells
- Macrophage activation
- Some B-cell activation
- Production of IgG1 (Opsonizing aby)
APCs activating CD4 TH2-Cells
- B-cell activation and antibody secretion
Structure of a CD4 Cell
- How does the structure help stabilize MHC:TCR binding
- What does it bind to
4 Domains, that forms a L shape
- Leans over and binds to β2 domain of MHC Class II to stabilize it
T-Cell Homing Process
- Circulating Lymphocyte enters the endothelial venule of the Lymphoid tissue
- L-Selectin on the lymphocyte binds with addressins (GlyCAM-1 and CD34) on the blood vessel barrier
- Lymphocytes starts rolling across the surface of the endothelial cell
- Lymphocyte grips other addressin molecules and slowly becomes immobilized
- Starts the process of Diapedesis, where the lymphocyte is squeezed between the tissue
- Lymphocyte has left the blood circulation and now enters the lymph node
What response does a T-Cell give if it does not recognize an antigen but is co-stimulated
No effect on T-cell
For an effect to occur the following needs to happen:
- TCR needs to recognize the antigen and the MHC,
- CD28 needs to receive a co-stimulatory response by B7
What contributes to MHC diversity
- Genetic Polymorphism
- Meiotic Recombination by inter-allelic conversion
- Segmental Exchange by Gene conversion
- Point Mutations
What are the four structural classes of Leukocyte Adhesion Molecules
- What are there functions
Selectins
- Found on Leukocytes (Lectins), binds to addressins
Vascular on Endothelial Cells around Lymph Nodes
- Vascular Addressin (Mucin), grips the selectin and pulls in the Leukocyte
Leukocyte Integrin Receptors
- Facilitate cellular movement at the lymph node
Inter-Cellular Adhesion Molecules (ICAMS)
- Makes endothelial vessels more leaky allowing cells to enter the lymph node
CD2: Lymphocyte Antigen (LFA)
How do B-Cells use Co-stimulatory signals
- B-Cells bind and internalize specific antigens
- Once activated B-cells process the antigen and synthesize MHC and B7
- Antigen-derived peptides (MHC) are selectively presented on the B-cells surface
- B7 is expressed on Cell surface
- T-Cells recognize the MHC:Antigen complex
- T-Cells recognize the B7 ligand through CD28 receptors
Where are Antigen Presenting Cells
Meet and reside in secondary lymphoid tissues
Dendritic Cells: T-Cell Areas
Macrophage: Follicles
B-Cells: Germinal Centres
Where are the alpha and beta chains assembled
In the Endoplasmic Reticulum
What do TCRs recognize
Recognizes the presented peptide and the MHC molecule
- This co-recognition is called MHC restriction and is highly specific
Specific TCRs are specific for one isotype and for one antigen
T Cell is only activated when it recognizes both the HLA Isotype and the Peptide Antigen
For the TCR polypeptides which locus is located in what other locus
Delta locus is located within the Alpha locus
What are the Professional Antigen Presenting Cells
- Order them by importance
- Dendritic cells
- Macrophages
- B-Cells
What kind of MHC do B-Cells have
Express both Class I and Class II
How are T-Cells activated by APCs
Needs a signal from the Antigen binding to the TCR and a signal from the co-stimulatory receptors (CD28)
What are the two primary classes of α:β T-Cells
Helper T-Cells (CD4 T-Cell)
Cytotoxic T-Cells (CD8 T-Cell)
MHC and Invariant Chains
- As the MHC Class II moves from the ER to the vesicle the invariant chain blocks binding of peptides to MHC class II
- This invariant chain also guides the MHC class II molecule out of the ER
- In the vesicle the invariant chain is cleaved, however, a small CLIP fragment remains bound
- CLIP blocks any peptides from binding to MHC class II in the vesicles
- HLA-DM facilitates the release of CLIP, allowing peptides to bind to MHC class II
- MHC class II is then transported by the vesicle to the cell surface where it can then express the antigen
What kind of MHC do Red Blood Cells express
None
Process of Antigen Presentation in Cell Mediated Immunity
- At the site of infection Dendritic Cells and Macrophages carry antigens from site of infections
- Antigens are carried through lymphatics to secondary lymphoid tissues
- T-Lymphocytes home in on secondary lymphoid tissues and leave circulation
- Antigens interact with T-Lymphocytes
How many MHC Class 2 Isotypes are there?
- What are they?
5 Isotypes
HLA-DM, HLA-DO, HLA-DP, HLA-DQ, HLA-DR
- The 2 stalks are represented by 2 letters
Immature vs Mature APC
Immature APC have dew MHC and few B7 Costimulatory Factors
- APCs have innate immune response surface receptors that can recognize foreign microbes
Once these receptors are activated B7 expression is induced and MHC is upregulated
Where are MHCs found
Major Histocompatibility Complexes are found on every cell except erythrocytes
Cytotoxic T-Cell Activation
Dendritic Cells and T Helper Cells activate CD8 T-Cells into cytotoxic effector cells
- CD8 cells program apoptosis into target cells through membrane-bound FAS ligand which activates caspase enzymes causing cell death
- CD8 cells release lytic granules like perforins and granzymes that help mediate cell destruction
What kind of MHC do Brain cells express
Express some Class I
Process of Antigen being carried to Lymphoid Tissue
- Dendritic cells take up bacterial antigens
- Then moves into a draining lymphatic vessel
- Dendritic cells with the bacterial antigen settle in the T-cell areas
What do TCRs interact with?
Major Histocompatibility Complex
- MHC bind to Peptide Antigens and present them to TCRs
What kind of MHC do epithelial cells of the thymus have?
Express majority Class Ii and a tiny bit of Class I
What are effects of different MHC isotypes
Changes the range of peptides they bind and the extent of genetic polymorphism
What is the function of a CD Glycoprotein
CD4 and CD8 Co-receptors help stabilizes the interaction between MHC and TCR
MHC and Autoimmunity
When no infection is present the only peptides that MHC Class I carry from the cytosol are from self-proteins
- Usually does not provoke an immune response (T-Cell Negative Selection in the Thymus)
Sometimes self-tolerance fails causing autoimmune disease
Interallelic Conversion vs Gene Conversion
Interallelic Conversion:
- Recombination of alleles on the same gene
Gene Conversion
- Segmental exchange of alleles on different genes
MHC Class I
- Where are they found
- What do they form complexes with
- What receptors do they present their antigens to
Found in all nucleated cells
Forms complex with endogenous antigens
Presents antigens to Cytotoxic T-Lymphocytes (CD8)
Do MHC proteins have high or low polymorphisms
- What causes this?
MHC protein products are highly polymorphic due to many possible combinations of multiple genes and alleles
Process of Inhibition of T-Cell Activation
CTLA4 and CD28 are both expressed by T-cells
- CTLA4 binds 20 times more strongly to B7 than CD28
CTLA4 binding inhibits B7 activation and prevents proliferation of T-cells
Function of Antigen Presenting Cells
Present Antigens to naive T-Cells using surface co-stimulatory CD glycoproteins (B7)
What is MHC incompatability
The leading cause of tissue graft rejection and graft-versus-host disease
What does IL-2 do to T-cells
Activates them by binding to high affinity IL-2 receptors
- Inducing T-cell proliferation
Structure of a CD8 Cell
- How does the structure help stabilize MHC:TCR binding
- What does it bind to
Two stalks (α and β) that are disulfide bonded together
- Line up with β2 Microglobulin and binds to α3 domain of MHC Class I
Which Human MHC Class I and Class I Isotypes have few polymorphism
Class I
- E, G
Class 2
- DM, DO, DR
What kind of MHC do T-Cells have
Resting T-Cells only have Class I
Activated T-Cells express Class I and a tiny bit of Class II
MHC Class I
- Processing and Presentation process of antigens
- Intracellular antigen is processed by proteasome into peptides
- Transporter TAP moves peptides into the Endoplasmic Reticulum
- Peptides bind to MHC Class I in the ER
- Peptide:MHC class I complex is then transported to the cell surface through the Golgi apparatus
- MHC class I presents peptide at cell surface
What contributes to TCR diversity
Genes that encode for the alpha and beta chains are fragmented in a germline configuration
- RAG enzymes rearrange gene segments to produce diversity and a highly specific receptor
What kind of MHC do Macrophages have
Express both Class I and some Class II
What Co-Receptors is specific for each MHC class
CD8 is specific to Class I
CD4 is specific to Class II
What kind of MHC do Neutrophils express
Express only Class I
What are the two classes of MHCs
Class I: Expressed on all nucleated cells
Class II: Found on antigen presenting cells of the immune system
- Thymus Epithelial Cells
- Lymphocytes
- Professional Antigen Presenting Cells
Structure of MHC Class I Molecule
1 Protein Chain forms the peptide binding groove
- α1, α2, α3
Protein Chain is stabilized by β2 Microglobulin
What are the two types of TCR
Alpha:Beta
Gamma:Delta
- Cancer Surveillance
- Determining friend and foe
T-Cells only one express on or the other
What is the specificity of MHC?
Degenerate Peptide Binding Specificity
- Can bind a large range of peptides
MHCs are not receptors, they are just molecules with a peptide binding groove
Which Human MHC Class I and Class I Isotypes have high polymorphism
Class I Isotypes:
- A, B, C
Class II Isotypes:
DR Beta
High amounts of specificity, can bind to a lot of derived antigens
What kind of MHC do Other Antigen Presenting Cells have (Dendritic Cells)
Express both Class I and Class I
What is the general structure of a TCR
Constant and Variable regions
2 Polypeptide chains that are disulfide linked
- alpha and beta chains (1 binding site)
What facilitates the Homing process of naive T-cells to tissues
Leukocyte Adhestion Molecules
TCRs vs BCRs
T-Cell Receptors recognize antigens presented to them from MHCs
B-Cell Receptors will bind to epitopes from antigens
- Proteins, Carbohydrate, Lipids (Macromolecules)
- Surface of organisms, soluble toxins
What do B-Cells Express?
What do T-Cells Express
B-Cells:
- Surface Immunoglobulin (BCR)
T-Cells:
- T-Cell Receptor (TCR)
- Cluster of Differentiation Glycoprotein
(CD4 and CD8 that stabilize MHC)
- CD28 and CTLA4 (Receptors that receive co-stimulatory signals)
Structure of MHC Class II Molecule
2 Protein Chains form the peptide binding groove
- α1, α2, β1, β2
