Exam 1: Antigen Processing and T-cell Development Flashcards
Target Cells
vs
APC’s
Professional antigen-presenting cells (APCs) display peptides on class II MHC molecules to CD4+ helper T-cells.
Target cells present peptides on class I MHC to CD8+ cytotoxic T-cells.
Cytosolic Pathway
Characteristics
- Class I MHC presents endogenous antigens
- Peptides can be any protein which have been synthesized in the cytoplasm of the cell:
- viral components
- intracelluar bacteria
- altered self proteins
- normal self proteins
- typically does not trigger an immune response
- Recognized by CD8+ cytotoxic T-cells
- Site of activity is the target cell
Cytosolic Pathway
Mechanism
- Endogenous Ag degraded within the cytoplasm by a proteasome.
- Cytosolic peptides trasported by TAP (transporter associated with atigen processing) into the RER.
- Class I MHC α-chains synthesized and associated with β2-microglobulin through chaperone-mediated interactions in RER.
- Class I MHC loaded with peptide and moves from RER to Golgi to plasma membrane.
Endocytic Pathway
Characteristics
- Class II MHC binds peptides which have been phagocytized or endocytosed from the extracellular environment.
- Any protein which was synthesized elsewhere and subsequently taken in by APC could be expressed on MHC II.
- If protein seen as “non-self” it can be recognized by CD4+ helper T-cells.
- Once activated Th cells will synthesize cytokines that regulate cellular & humoral immunity.
- Site of activity is the professional APC.
Endocytic Pathway
Mechanism
-
Exogenous Ag taken up by phagocytosis, endocytosis, or pinocytosis depending on the APC.
- Waits for MHC II molecules
-
Class II MHC α- and β-chains synthesized in the RER and associated with the invariant (Ii)-chain
- guides MHC where it needs to go
- blocks the binding grooves so peptides cannot be loaded
- αβIi complexes transported through Golgi to endosomes and lysosomes
- Invariant chain progressively degraded ultimately leaving only CLIP (class II-associated invariant chain peptide) in the peptide binding groove
- CLIP removed and exogenous peptide from endosome or lysosome added
- Peptide-loaded class II MHC transported to plasma membrane
Antigen-processing Pathways
Summary
If a peptide is recognized as foreign on class I MHC by CD8 T-cells it signals that there is a problem within this cell ⇒ kill the cell.
If a peptide is recognized as foreign on class II MHC by CD4 T-cell it signals that there is a problem within the body ⇒ produce cytokines to help activate/modulate the immune system.
All antigens must eventually go on MHC II to activate a proper immune response.
Vesicular Pathogens
- Some microbes have evolved to resist the microbicidal activites of phagocytes.
- Ex. Tuberculosis, protozoa
- Can survive and replicate within the phagolysosomes.
- Since pathogens exist in the source compartment for class II MHC, peptides are located onto MHC II despite being produced within the cell.
- Stimulates IFN-γ production by CD4 T cells.
- IFN-γ promotes macrophage activation and killing.
- Stimulates granuloma formation if cannot kill.
- Some of these microbes may enter the cytoplasm of infected cells and divide there so loaded onto MHC I.
- When cytotoxic cells try to kill them may just distribute pathogen upon lysis.
Issues with MHC
MHC unable to discriminate between foreign and self antigens.
- Concentration of self-proteins will outnumber microbial or “altered self” antigens.
- Virally infected cells make IFN α/β within hours of infection.
- Stimulates MHC I production
- High concentration of viral Ag allows Ag loading onto newly synthesized MHC I ⇒ Activates CD8 T-cells.
- MHC molecules are constantly displaying self-antigens.
- TCR has induced tolerance which prevents autoimmunity.
T-cell Development
Overview
- Bone marrow progenitor cells (Pro-T cell expressing CD2) migrate to the thymus gland
- Immature cells enter the cortex and mature as they travel towards the medulla.
- Mature naive T cells leave thymus through peripheral blood circulation and travel to 2° lymphoid organs
- Cells populate 2° lymphoid organs where they can encounter Ag and exert effector functions
Thymus
-
Primary lymphoid organ for T-cells
- Shrinks after puberty or corticoid exposure
- As thymocytes (developing T-cells) move from cortex to medulla they become more mature and express different surface markers
- Direct contact with:
- Non-lymphoid thymic stromal cells
- Soluble and membrane-bound factors
- Bone marrow derived interdigitating dentritic cells
- Aids thymic education (selection)
- Non-lymphoid thymic stromal cells
- Thymic microenvironment directs T cell development through direct cell-cell contact and cytokines
- Which cytokine they encounter determines the type of T cell they become
T-cell Differentiation
- Pro-T cells (CD2+, CD7+) migrate from bone marrow to thymic cortex.
-
TCR rearrangement forms pre-T cells.
- Express low levels of TCR and CD3.
- No CD4 or CD8 yet = double negative cells (TCR+low, CD3+, CD4-, CD8-)
- Following TCR expression, both CD4 and CD8 are coexpressed to produce double positive cells (TCR+low, CD3+, CD4+, CD8+)
- Thymic education occurs
-
Positive selection
- Ensures that T cell can bind peptides on MHC molecules
- Bindings results in a “to live” signal
- Can only recognize Ag when bound to the same MHC encountered in the thymus = MHC restriction
-
Negative selection
- Removes cells that recognize self-peptides bound to MHC
- Autoreactive cells get a “to die” signal
- Failure results in potentially auto-reactive T cells
-
Positive selection
- Thymic education occurs
- Cells which survive selection down regulate either CD4 or CD8 to become single positive cells.
- These cells upregulate expression of αβ TCR molecules.
- Become either mature Th cells or mature Tc cells.
- Mature naïve T cells enters circulation and travel to 2° lymphoid organs or back to bone marrow.
MHC Polymorphisms
- Allelic forms of MHC I & II expressed determines which peptides can be presented.
- Also determines which T cells survive positive and negative selection.
- Suggests that there is a genetically predetermined capacity to react immunologically against a given immunogen.
- Plays a role in individual immune responses leading to resistance or susceptibility to infection & autoimmunity.
- Usually only a few epitopes from any antigen or pathogen can be presented effectively to a T cell.
- Expression of multiple MHC genes increases likelihood of success.
- Polymorphism provides protection for species at large.
Autoimmunity
MHC alleles have been linked to autoimmune disease.
No HLA allele associated with 100% of cases so probably only one of the factors involved.