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4_antigen_recognition_by_lymphocytes.md

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Antigen Recognition by B-cell and T-cell receptors

T cell antigen recognition

TCRab ~= Fab antibody fragment

Each chain is two Ig domains and they are linked by a disulfite bond

They have a variable and constant domain with homology to the immunoglobulin analogues from antibodies. Cysteine stalk with a disulfite bond.

CDR loops are roughly the same as in antibodies. (Ex: of difference - CDR2 in beta chain is at a different angle)

There is HV4

TCR recognizes peptide:MHC complex

Recognize short continuous peptide sequences presented from MHC

Two types of MHCs with different structures

I

  • Three domains from alpha chain and one beta_2 microglobulin
  • Alpha_1 and alpha_2 form the peptide binding cleft
  • Only alpha chain spans the membrane

II

  • two membrane spanning alpha and beta chains
  • ends of the peptide binding cleft are more open

Peptides stabilize MHC molecules

MHC are only stable when bound to peptides and this makes their presence on the surface of a cell a reliable indication of infection.

MHC 1 bind short peptides (8-10 aa)

Peptide fragments are locked in place by their free amino and carboxyl to the peptide binding groove.

(Synthetic peptides lacking these free ends are unable to bind)

MHC 1 is highly polymorphic and allelic variation presents itself along the peptide binding cleft

The key amino acids that contribute to affinity along the groove are called anchor residues.

MHC 2 bind unconstrained peptides

Bound peptides >= 13 aa. MHC 2 proteins lack the conserved regions at the ends of the cleft that bind the peptides in place.

Also have same anchror resiudes amongst families of sequences that bind

peptide:MHC:TCR complexes have a unique structure

The entire TCR is rotated slightly when it binds to MHCs.

Valpha is roughly on top of amino terminal while Vbeta is roughly on top of carboxyl terminal

Induces some amount of conformational change of receptor - "moving the CDR loops" to slot into grooves of the peptide / cleft structure.

CD4 / CD8 molecules are TCR coreceptors

Bind simultaneously with the TCR / MHC peptide groove.

CD4 is expressed on "helper" Tcells. (MHC 2) CD8 is expressed on "cytotoxic" Tcells. (MHC 1)

CD4 is a chain of 4 immunoglobulin domains and binds to MHC2 at the hydrophobic cleft formed by the beta_2 and alpha_2 domain

CD8 is a disulfide linked pair of chains (alpha / beta) with a long, glycosylated polypeptide chain attaching it to the membrane. (The glycosylation is thought to maintain its conformation and keep it from getting digested).

Binds more weakly to the alpha_3 domain of MHC1 and the binding affinity is effected by the amount of glycosylation.

MHC cell type expression distribution

MHCII expressing cells are usually themselves the immune cells that are modulated by CD4+ T cells.

eg. B cells that will change antibody isotype or macrophages that become "activated"

MHCIIs are expressed in:

  • B cells
  • Dendritic
  • Macrophages
  • Neutrophils

Most tissues, including the above, express MHC I. Including kidney, liver, etc.

Neither are expressed on non-nucleated (eg. blood cells)

gamma/delta TCRs are unique

Misc. Questions

Why is CDR3 the loop with highest variability?

Has the greatest contact with the peptide during the peptide:MHC:TCR binding. Also has greater combinatorial diversity by the inclusion of the D region during somatic hypermutation.

Why is Fc crystalizable but Fab not?

Overview of the crystallography process?

  • Purification
  • Construction of a "crystal" - repeated lattice structure
  • Crystal growth
  • Crystal mounted on a goniometer in front of an xray source

Why did camelids evolve heavy chains?

extreme environments:

  • thermal stability
  • less resources to manufacture

What are the tx benefits of heavy chains only?

  • Smaller / easier to traffic to tissues
  • More stable
  • Cheaper to manufacture and easier to engineer
  • Less immunogenic (look less like a different human's antibody?)

Specific examples of antibody <> epitope interactions for each of the bond types.