April 1 Notes

Here is a quick video of T-cell Activation if anyone needs it: http://www.youtube.com/watch?v=tqjhMHG7J08
Chapter 4: MHC and T-cell Activation

I. A review of role of T-cells in adaptive immunity
a. Adaptive vs. Innate immunity
Adaptive: recognizing microbial chemicals that are NOT shared by many kinds of microbes
-takes more time than innate immunity
-much more flexible
Innate: Probably more important than adaptive immunity
-always on
-NOT flexible
b. T-cell receptors
-constant region: attaches to cell membrane, used for signal transduction from outside of membrane to inside of cell
-variable region: attaches to antigen, different for EACH T-cell
c. CD8+ T-cells (cytotoxic)
-release enzymes that lyse infected cell
-MHC I w/ co-receptor CD8+
d. CD4+ T-cells
i. Interact with macrophages and B-cells: present antigens to APC stimulate antibody release
ii. MHC class II
iii. CD4 as co receptor

Host vs. graft disease:
-everyone has different MHCs
-foreign MHC I is recognized by CD8 T-cell receptors as MHCI presenting foreign antigen
-So, CD8+ T-cells kill "virally" infected cell

II. Dendritic Cells
a. Immature
- Hang out in tissues for a few days or weeks
- globular shape
- constantly sampling environment through phagocytosis and lots of macropinocytosis
b. spontaneously matures, becomes star-shaped, expresses CCR7, CCR7 leads to migration to lymph nodes
- In lymph nodes, mature dendritic cells present antigens from cell debris to T-cells
- Though that presentation of antigens by mature, but not "activated" dendritic cells helps maintain
tolerance to own antigens
c. Mature, activated
i. Immature D.C. sampling environment
ii. Detects microbial components via TLRs or pro-inflammatory cytokines (IL1, TNF) via receptors for them
iii. Leads to: increase in phagocytosis & macropinocytosis & increase MHC II , some increase MHC I, expression of costimulatory molecules (molecules that help activate T-cells) (here, B7 family = costimulatory proteins
iv. B7-costimulation of T-cells how T-cells “know” this dendritic cell is presenting foreign, not self antigens
III. Major histocompatibility complex (MHC) molecules
a. Classical vs. non-classical MHCs:
i. Classical MHC’s: directly involved in presenting antigens to T-cell receptors
1. MHC 1 and MHC II
ii. Non-classical MHC’s: don’t present antigens; cytoplasmic proteins that help load antigens onto classical MHCs
b. Diversity of MHCs:
i. Layout of MHC alleles in MHC gene complex: a lot of α & β chain alleles: MHC components very
polymorphic»500 α chain alleles, so no one is likely to be homozygous for α-chain alleles (picture in notes)
ii. Evolution of MHC diversity: advantageous to have a lot of variability in MHC antigen-binding sites b/c this
allows a population of humans to bind more variable antigens, fight wider array of pathogens
c. Structure of MHC 1
i. Alpha Chains: 3 combine to make MHC I; α3 attaches MHC 1 to connects to cell membrane
1. β2-microglobulin: stabilizes α chains; little/no variability in β2 microglobulins among people
ii. Peptide Binding grove: where peptide (antigen to be presented to T-cell) is attached to MHC I
1. MHC I peptide binding groove binds peptides only 8-10 amino acids in length b/c MHC I is wrapped
around the peptide it is presenting
iii. Consensus binding sites: a few amino acids in a few spots seem to be necessary for MHC I-peptide binding
d. Structure of MHC II
i. Alpha and beta chains: 2 α-chains & 2 β-chains; both interact with cell membrane
1. Chain interaction forms peptide binding groove
ii. Peptide binding groove: does not have consensus anchor sites on peptides bound by
1. Can bind peptides ~20 amino acids in length
IV. Loading of peptides onto MHCs
a. “chaperone protein”: proteins that hold nasecent (newly formed) proteins in correct shape so they’ll fold correctly
b. MHC I: mRNA translated by ribosomes attached to ER
i. α-chains of MHCI unstable w/o peptide bound to peptide-binding groove
ii. so chaperone proteins bind to protect new NHC I until peptide binds to it
1. peptide in cytoplasm of cell b/c that’s where pathogen was then pathogen proteins cleaved into
peptides that fit MHC I
2. enzymes that cut up pathogen proteins = proteasome: in cytoplasm; proteasome interacts w/ER
allows transport of peptides across ER membrane, where ca be loaded onto MHC I
iii. Presents intra cellular path. parts to CD8+T-cells
iv. MHCI + peptide blebs of ER in vacuole, transported to cell surface where vacuole membrane integrates w/
cell membrane
c. MHC II: similar to MHC1
i. MHC II protein binding groove also need a protein bound to them to be stable
ii. Peptides from extracellular pathogens
iii. Pathogens/path. parts must be phagocytosis; vacuoles will contain the parts
iv. Vacuole containing pathogen peptides fuses w/vacuole from lumen of ER containing MHC II
1. MHC II is stabilized by binding CLIP in peptide binding groove
2. CLIP-MHC II binding weak, easily displaced by peptide complementary to peptide-binding groove
V. Antigen presentation by dendritic cells
a. TLR or cytokine receptor binding to ligand -> lots of phagocytosis by dendritic cell
b. This -> increase MHC expression
c. After phagocytic burst, few round of great increase MHC expression, MHC expression shut down
d. Then, activated, mature dendritic cell migrates to 2° lymphoid tissues
*stronger interaction betwen foreign-presented material in MHC's and tCRs

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