Download Major histocompatability complex (MHC) and T cell receptors

Major histocompatibility complex
(MHC) and T cell receptors
Jennifer Nyland, PhD
Office: Bldg#1, Room B10
Phone: 733-1586
Email: [email protected]
Teaching objectives
• To give an overview of role of MHC in immune
response
• To describe structure & function of MHC
• To describe structure & function of TCR
• To discuss the genetic basis for generation of
diversity in TCR
• To describe the nature of immunological synapse
and requirements for T cell activation
Role of MHC in immune response
• TCR recognizes Ag presented in MHC
– Context is important
– Binding of Ag peptides in non-covalent
• Two types of MHC (class I and class II) are
recognized by different subsets of T cells
– CTL recognizes Ag peptide in MHC class I
– T-helper recognizes Ag peptide in MHC class II
Structure of MHC class I
• Two polypeptide
chains
– Long α chain and
short β
Structure of MHC class I
• Four regions
– Cytoplasmic contains sites
for phosphorylation and
binding to cytoskeleton
– Transmembrane contains
hydrophobic AAs
– Highly conserved α3
domain binds CD8
– Highly polymorphic
peptide binding region
formed by α1 and α2
Structure of MHC class I
Ag-binding groove
• Groove composed of
– α helix on 2 opposite
walls
– Eight β sheets as floor
• Residues lining floor are
most polymorphic
• Groove binds peptides
8-10 AA long
Structure of MHC class I
Ag-binding groove
• Specific amino acids on peptide are required
for “anchor site” in the groove
– Many peptides can bind
– Interactions at N and C-terminus are critical and
“lock” peptide in grove
– Center of peptide bulges out for presentation
– Consideration in vaccine development
Structure of MHC class II
• Two polypeptide chains
– α and β
– approx equal length
Structure of MHC class II
• Four regions
– Cytoplasmic contains sites
for phosphorylation and
binding to cytoskeleton
– Transmembrane contains
hydrophobic AAs
– Highly conserved α2 and
β2 domains binds CD4
– Highly polymorphic
peptide binding region
formed by α1 and β1
Structure of MHC class II
Ag-binding groove
• Groove composed of
– α helix on 2 opposite
walls
– Eight β sheets as floor
– Both α1 and β1 make up
groove
• Residues lining floor are
most polymorphic
• Groove binds peptides
13-25 AA long (some
outside groove)
Important aspects of MHC
• Individuals have a limited number of MHC
alleles for each class
• High polymorphism in MHC for a species
• Alleles for MHC genes are co-dominant
– Each MHC gene product is expressed on surface of
individual cell
Important aspects of MHC
• Each MHC has ONE peptide binding site
– But each MHC can bind many different peptides
– Only one at a time
– Peptide binding is “degenerate”
• MHC polymorphism is determined in germline
– NO recombination mechanisms for creating
diversity in MHC
• Peptide must bind with individual’s MHC to
induce immune response
Important aspects of MHC
• How do peptides
get into MHC
groove?
golgi
Class I
– Class I: peptides
in cytosol
associate with
MHC
Peptide in vesicle– Class II: peptides
Displaces Ii chain from within
vesicles
associate with
MHC
Ii chain
Class II
ER
Important aspects of MHC
• MHC molecules are membrane-bound
– Recognition by Ts requires cell-cell contact
• Mature Ts must have TCR that recognizes
particular MHC
• Cytokines (especially IFN-γ) increase
expression of MHC
T cell receptor (TCR)
Role of TCR in immune response
•
•
•
•
Surface molecule on Ts
Recognize Ag presented in MHC context
Similar to Immunoglobulin
Two types of TCR
– α β: predominant in lymphoid tissues
– γ δ: enriched at mucosal surfaces
Structure of the TCR (αβ)
• Heterodimer
– α and β chains
– approx equal length
Structure of the TCR (αβ)
• Regions
– Short cytoplasmic tailcannot transduce
activation signal
– Transmembrane with
hydrophobic AAs
– Both α and β have a
variable (V) and constant
(C) region
– V region is hypervariable,
determines Ag specificity
Important aspects of TCR
• Each T cell has TCR of only ONE specificity
– Allelic exclusion
• αβ TCR recognizes Ag only in the context of
cell-cell interaction and in correct MHC
context
• γδ TCR recognizes Ag in MHC-independent
manner
– Response to certain viral and bacterial Ag
Genetic basis for receptor generation
• Accomplished by recombination of V, D and J
gene segments
– TCR β chain genes have V, D, and J
– TCR α chain genes have V and J
TCR and CD3 complex
• TCR is closely associated
with CD3 complex
– Group of 5 proteins
– Commonly called
“invariant” chains of TCR
• Role of CD3 complex
– CD3 necessary for cell
surface expression of
TCR
– transduces signal after
Ag interaction with TCR
The “immunological synapse”
• TCR-MHC interaction is
not strong
• Accessory molecules
stabilize interaction
– CD4/MHC class II or
CD8/MHC class I
– CD2/LFA-3
– LFA-1/ICAM-1
The “immunological synapse”
• Specificity for Ag is
solely in TCR
• Accessory molecules
are invariant
• Cytokines change
expression levels
The “immunological synapse”
• Co-stimulation is also
necessary for activation
of T cells
– CD28/CD80 or CD86
• CTLA-4 on T cells can
also ligate CD80/CD86
– Inhibitory signal
– downregulation
Key steps in T cell activation
• APC must process and present peptides to Ts
• Ts must receive co-stimulatory signal
• Accessory adhesion molecules stabilize
binding of TCR and MHC
• Signal from cell surface is transmitted to
nucleus
• Cytokines produced help drive cell
proliferation