Flashcards in Lecture 7 - Antigen presentation and MHC Deck (31):
What are the different types of antigen presenting cells?
Which of these is NOT phagocytic?
Which class are these molecules, Type I or Type II?
1. Mononuclear phagocytes
- kuppfer cells in liver
- microglial in CNS
- in tissue = macrophages
2. Dendritic Cells
- Skin = langerhan's cells --> present antigen in lymph organs from the skin (after joining T cell)
3. B lymphocytes
- lymphoid tissue
- sites of immune reaction
B LYMPHOCYTES ARE NOT PHAGOCYTIC
** All are Type II**
What are the 2 distinct lineages of dendritic cells?
What is there respective function?
- undergo maturation from immature to mature DX
- immature = phagocyticc
- mature = antigen presenting (peptide) in context of MHC II
- produce interferon in response to via infections
When is B lymphocyte antigen presentation most important?
During secondary antibody responses
What happens to conventional dendritic cells as they mature?
They go from highly phagocytic to non-phagocytic and presenting large quantities of peptide to MHC II molecules. Mature cells also have lots of co-stimulatory molecules and can produce cytokines and can present antigen very well to T lymphocytes.
When does association of antigenic fragments occur?
Following cytoplasmic production (ClassI) of the antigen or alternativey following phagocytosis or endocytosis (Class II) of the antigen
Describe the major steps in MHC Class I antigen presentation pathway (4)
1. Virus infects cell
2. Viral proteins made in cytosol
3. Peptide fragments of viral proteins bound MHC class I in ER!
4. Bound peptides transported by MHC Class I to the cell surface
State which is Class I and which is Class II
MHC Class ___takes place following cytoplasmic production.
MHC Class ___ takes place following phagocytosis or endocytosis of the antigen.
What are the 6 key steps of the MHC Class II pathway?
1. Antigen is taken up from extracellular space to intracellular vesicle
2. Early endosome (neutral pH) endosomal proteases are active
3 Acidification of vesicles --> degrade antigen into peptide fragments
4. Vesicles of peptide fuse with vesicle of MHC II
5. Antigen spcific B cell binds Antigen
6. Specific Antigen internalized by receptor mediated endocytosis
7. High density of specific antigen fragments presented
What is responsible for transporting peptides generated in the cytoplasm into the ER during MHC Class I presentation?
TAP-1 and TAP-2
- viral antigenic peptides produce viral proteins that are degraded by cell's proteasome, into small peptide fragments
- peptides made in cytoplasm are transported into ER by TAP 1 and TAP 2
What happens after newly made MHC Class I molecules assemble in ER with several chaperones and then transported to ER by TAP1/TAP2?
1. Trimmed by ERAAP
2. peptides bind MHC
3. protein- MHC complex leaves ER and is transported through golgi to the cell surface
What are the 4 key steps of antigen processing for Class II presentation?
1. Antigen taken up from EC space into IC vesicles.
2. early endosomes have neutral pH and inactive proteases
3. Acidification of vesicles activates proteases to degrade antigen and peptide fragments.
4. Vesicles containing peptides fuse with vesicles containing MHC Class II.
Where are MHC Class II molecules made?
What is bound in the peptide binding cleft?
Acidification of endosome shortens this molecule and leaves _____
What releases this molecule from the peptide binding site?
Made in ER and transported to endosomes with associated protein (invariant chain)
3. CLIP (in the peptide binding groove)
4. HLA - DM binds to class II molecule and releases CLIP
- it then travels to the cell surface
Under normal conditions, what are MHC Class I and MHC Class II molecules loaded with?
(What is the difference between MHC Class I and Class II in terms of how they are normally loaded with proteins?)
MHC Class I - self peptides
MHC Class II - CLIP
MHC I molecules are normally loaded with self peptides. MHC II molecules contain only CLIP.
What do CD4+ T lymphocytes not recognize?
What do they recognize?
Soluble antigens or free antigens
Recognize antigen on surface of APC's
What is the following termed:
Genetically restricted by Class II molecule on which antigenic determinants was first recognized.
Interaction of T lymphocyte and antigen and Class II molecule is highly specific and will result in specific T cell proliferation and differentiation
What can CD4+ T lymphocytes mediate?
Macrophage activation or act as helper cells (by secreting cytokines)
What do the following CD4+T lymphocytes do:
- activate macrophages
- induce antibody synthesis
Which cells (mature or immature) dendritic cells produce co-stimulatory molecules or cytokines like B7? (APC)
Mature Dendritic cells!
What 2 signals are required for activation of a naive T cell?
1. presentation of peptides by MHC
2. interaction between B7 on APC and CD28 on T cell membrane
When an APC does not express B7, how do the cells get around this?
T cells that recognize peptides expressed by MHC class II on the APC surface are stimulated to express CD40 ligand, CD40L.
CD40L engages CD40 on the APC surface to induce B7 expression by the APC.
What induces T cell proliferation and differentiation?
CD28 ligation on T cell with B7 on APC
Summarize the steps in T cell mediated B cell activation (4 steps)
1. B cells take up antigen, process it, and display the processed peptides on MHC Class II molecules.
2. B cell makes B7, which costimulates CD28 on the surface of a T cell that recognizes the antigen on MHC II
3. CD40L expression is induced.
4. CD40L engages CD40 on the B cell surface, activating the T cell to produce cytokines, and allowing B cell proliferation.
What mechanism is used for sustained TCR engagement (especially necessary for T ell proliferation)?
What is the general structure of a mature immunological synapse?
central cluster of TCRs surrounded by ring of adhesion molecules like LFA-1
What is the purpose of adhesion molecules like LFA-1?
promote efficient TCR-MHC-peptide interaction in the immunological synapse.
Where is LFA-1 located?
Where is I-CAM-1 located?
What is contained in the inner circle of the immunological synapse? T
T cell surface.
- inner circle contains TCR, CD4, and co-stimulatory molecules like CD28
Why are MHC proteins so polymorphic; that is, why are there so many different MHC alleles?
MHC polymorphism ensures that a population will not succumb to a new or mutated pathogen because at least some individuals will be able to develop an adequate immune response.
Ex: malaria, bubonic plague
Compare MHC restriction for T helper and cytotoxic T lymphocytes. T
helper cells are restricted to Class II MHC antigens present on immune cells and help with the humoral response.
Cytotoxic T cells are restricted to Class I antigens presented on nucleated body cells and protect against virus and cancer.
Compare the various types of antigen presenting cells.
3 Major types are mononuclear phagocytes, dendritic cells, and B lymphocytes.
Only B lymphocytes are nonphagocytic.
All have MHC Class II.
Mononuclear phagocytes are in the blood (macrophages), liver (Kupffer cells) or spleen (macrophages)
Dendritic cells are in the skin (Langerhans) or lymphoid tissues (interdigitating or follicular).
B lymphocutes are in the lymphoid tissues and are sites of immune reactions.
Co-stimulatory molecule expressed on the surface of CD4+ T lymphocytes:
E. Non-polymorphic regions of class I MHC molecules C
CD4 and CD8 are not costimulatory molecules.
Further, CD8 will not be present on a single CD4+ T cells.
CD28 is a co-stimulatory molecule that activates T cells in conjunction with B7