Lec 6- Ag recognition by T cells Flashcards
T cells are like B cells because
- They are lymphocytes
- They develop in the bone marrow
- Have diverse Ag receptors on their surface
+Structutal similarities
+formed from gene rearrangement
+Only a single species of receptor exists on any one cell
T cells are Unlike B cells because
- They mature in the thymus
- Exert their effector function by interacting with other cells of the immune system
- They recognise different Ag
+Peptides +processed
+Presented with MHC
- They never release a soluble Ag receptor
- Their receptor doesn’t change on Ag recognition
Immunoglobulins- a reminder
- The Ag receptor of the B cell
- Ab’s (when soluble)
- Fab and Fc region
- Fc region
+talks to the rest of the immune system
-Fab region
+Binds Ag
T cell receptor (TCR)
-Alpha (a) chain and Beta b) chain -
variable region
- constant region
- transmembrane region (V.short cytoplasmic taiL)
- It resembles a membrane associated Fab fragment of an immunoglobulin
TCR
- Membrane bound glycoprotein- hetrodimer
- One Ag binding site (a and b)
- Ag binding at the top surface
- No class switching (IgG -> IgE) -variable and constant
- Hypervariable regions
+aka complementary- determining regions (CDR’s)
+Loops on tips
The Ig domain of the TCR
- This has b- pleated sheets
- At the top there are 3 CDRs for the alpha and beta
TCR diversity- gene rearrangement
- Happens pre-Ag
- Gene segments recombine for each chain
- DNA rearrangement
- Essentially using same mechanisms as for B cells (last time) BUT
- In B cells, after Ag the heavy chain constant regions could change- class switching
- This doesn’t ever happen with TCR’s
Gene rearrangement
- We have 2 germline DNA lines (one for a and one for b)
- This means that the repertoire for cell receptors is high than for Ab’s
- But the process is the same
- Thymus during development -a chain- like (V-J- light chain) -b chain- like (D,J,V- heavy chain)
- V(D)J recemobinase
+Recognises RSS (recombinant signal sequence
+Contain RAG and DNA modifying enzymes
-RAG is important (RAG1 and RAG2)
+Recombinant activating gene
SCID- severe combined immunodeficiency
- Lack of functional B and T cells (could be due to lack of RAG or recombinase)
- Opportunistic infections
- Lethal during infancy
+Unless treated
+BM transplant
-Various mutations can cause this including RAG defects
TCR diversity
- Rearrangement of gene segments (DNA)
- Transcription (RNA)
- Splicing (mRNA)
- Translation (RER)
- ER- association of a and b chains; transport to T cells surface
Extra proteins are needed for TCR expression
- TCR complex- required for exit from ER
- Four invariant chains required: CD3 complex (gamma, sigma and epsilon- these hold together the structure and encourage the binding of TCR to target);
Zeta chain (this is associated because the transmembrane part of the TCR is so short that they can’t communicate with the cell so the zeta chain allows for signal transduction)
- Held together with strong electrostatic interactions
- Signalling components of TCR -
- Defects here lead to immunodeficiency
Another T cell population
- We do have gamma-delta T cells
- We don’t no what they do
- They only make up 1-5% of T cell population
- Dont need to no how they work
T cell recognise processed and present Ag
- T cells are looking for peptide stuck on MHC
- Protein Ag in cell
- Ag processing by breakdown of protein
- Presentation of MHC with pathogen Ag
2 different classes of T cell and MHC
- CD4 = Class II MHC + peptide this is associated with Helper T cells
- CD8 = Class I MHC + peptide this is associated with cytotoxic T cells
Why 2 classes of MHC
-To deal with different pathogens
+Intracellular- virus’
+Extracellular- Bacteria
-To interact with different T cells i.e. helper or cytotoxic
T cells can help or kill: Kill
T cells function by making contact with other cells and inducing them to change
- CD8 T cell makes contact with infected cell MHC class I
- This combination leads to events where the T cell will kill the infected cells
T cells can help or kill: help Macrophages
- CD4 T cell and macrophage that has MHC class II presented on it’s surface
- They come into contact with one another
- Helper T cell will release cytokines
- Macrophage will then become activated and release cytokines of its own to then activate other immune cells (cascade)
T cell can help or Kill: help B cell
- CD4 T cell and B cell that has MHC class II on its surface
- The B cell and T cell come into contact, cytokines are released
- This turns the B cell into the plasma cell and the plasma cell will start releasing the immunoglobulin as Ab
MHC I and II- variaition on a theme
- Similar structure based on Ig domain
- Ig chain folding forms a peptide- binding groove
- MHC I- 1 MHC chain (AND b micro globulin)
- MHC II- 2 MHC chain
- MHC- supports peptide allows CD4/8 to bind
MHC binds to the co-receptor and TCR
- Target cell (virus infected cell)
- MHC Class I is produced and this helps bind with the TCR so it can recognise the Ag
- CD8 co-receptor is helping the stabilisation of the binding as well
- This is the same for CD4 but it is with MHC class II
MHC binding of peptide
- Promiscuity- means not very specific, but this is good because it means that we can bind many different peptides
- This limits the number of different MHC classes we need
- However because it can bind so many peptides it means that there is a chance that our own peptides could then be bound within the MHC
- If we didn’t have the T cell selection process it would react to our own peptides
Class I and Class II bind peptides from different cellular compartments
- Cells have 2 major compartments
- Cytosol- peptides from intracellular pathogens
- Vesicular systems- peptides from extracellular pathogens, even though the vesicle is in the cell the peptides are still classed as extraceulluar because there not in the cytosol
Class I loading- part 1
- Cytosolic proteins are degraded
- generates peptides
- transported into the ER lumen
- TAP (transporter of antigenic peptides)- transports class I type peptides
Class I loading- PART 2
- Chaperone holds MHC I chain until B2immunoglobulin binds
- Peptide loading complex formed
- TAP delivers peptide
- Complex dissociates vesicular transport of loaded MHC I to surface
Class I loading- part 3
- MHC class I is loaded with a peptide that is too long at the N terminus
- ERAP moves N-terminal amino acids to give a peptide of 8-10 residues
- MHCclass I molecule travels to cell surface
Class I MHC cannot leave the ER without a peptide
-Bare lymphocyte syndrome
+Non-functional TAP
+Peptides cannot enter ER
+Very low levels of surface MHC class I
- Low cytotoxic T cell response CD8
- Chronic respiratory infections, poor response to virus
MHC class I display self antigens to
- Degradation and transport of intracellular peptides occur continuously
- MHC class I displays peptides derived from normal, self proteins
- No immune response to these- unless self reactive T cells have been allowed to leave the thymus- AUTOIMMUNITY
The MHC class II pathway
- Extracullar Ag enters in an endocytic vesicle (phagosome)
- Peptide production in phagosome with lysosome fusion
- MHC II which is made in the Golgi apparatus then enters a vesicle and the 2 vesicles fuse
- Peptide and MHC bind (peptide loading)
- MHC class II is presented on cell surface
Invariant chain stops peptide binding to class II ER
- Invariant chain blocks binding of peptides to MHC class II molecules in the ER
- In vesicles invariant chain is cleaved, leaving the CLIP fragment bound (vesicle starts to become acidic)
- CLIP blocks binding of peptides to MHC class II in vesicles
- HLA-DM facilitates release of CLIP, allowing peptides to bind
MHC expression profiles- where we see it
- Class I- most human cells
- Class II- professional APC (B, macro, DC)
+Thymic epithelium for T cell testing
-Not on RBC so sometimes called HLA (not having this means blood transfusion is far easier than transplantation)
MHC expression
MHC MOLECULES -are polygenic (different gene families)
+Encoded by different gene families
+Class I and II a and II b
- Clustered in chromosomal region MHC
- Are polymorphic: different variants (Isotypes) each with different alleles (alloys
MHC expression
- Shows species and individual variation
- Human: 3 class I from each parent; 6 class I per cell
- Permits lots of different peptide presentation: prevents a population from being susceptible to a single infection (Cheetah not the case)
- MHC is the major reason for transplant rejection so a perfect match is needed- twins or clones
