05 - Adaptive Immunity (T Cell Receptors)

Adaptive Immunity: T Cell Receptors

tags: #immunology #cellbio
links: Bio 151 topic 4: T Cell Receptors

Two Responses of Adaptive Immunity

1. Antibody Responses
2. Cell-mediated Immune Responses

Cell-mediated immune responses

T lymphocytes or T cells and all cells (except erythrocytes)
major histocompatibility complexes (MHC) and T-cell receptors (TCR)
MHC class I
involves cytotoxic or CD8 T cells
deals with intracellular pathogens
requires CD8 receptors
MHC class II
involves helper or CD4 T cells
deals with extracellular pathogens
requires CD4 receptors
T-cell receptors
similarities with antibodies
α and β chains similar to light and heavy chains of antibodies respectively
variable and constant region
differences with antibodies
recognizes only short peptides unlike antibodies
short peptides presented by a major histocompatibility complex (MHC)
no differentiation or hypermutation after recognizing an epitope
no free-floating form
T-cell receptor diversity
 α-chain
chromosome 14
V and J segments
β-chain
chromosome 7
V, D, J segments
also involves RAGs
relies on DNA recombinations much like antibodies
only 1 Cα gene and 2 Cβ genes but both are functionally identical

Origins of diversity from transposons in innate immunity

Transposons
short gene segments that code for transposases → enzyme which cuts transposons
and copy and paste it to other parts of DNA
T-cell receptor complex
do not penetrate through membrane of T cells
rely on support proteins
CD3δ, CD3γ, CD3ε
ζ chain
functions in transducing signals since T-cell receptors have transmembrane
regions that do not penetrate cell membrane
transport of newly synthesized TCR to the cell surface
transduction of signals to the cell’s interior after the TCR has bound antigen
 The functional antigen receptor on the surface of T cells is composed of eight
polypeptides and is called the T-cell receptor complex. The α and β chains bind antigen
and form the core T-cell receptor (TCR). They associate with one copy each of CD3γ
and CD3δ and two copies each of CD3ε and the ζ chain. These associated invariant
polypeptides are necessary for the transport of newly synthesized TCR to the cell
surface and for the transduction of signals to the cell’s interior after the TCR has bound
antigen.
Two classes of T-cell receptors
α:β
chains similar in all jawed vertebrates
γ:δ
not similar in mice and humans
not as studied
 The α:β T-cell receptor (left panel) and the γ:δ T-cell receptor (right panel) have similar
structures, but they are encoded by different sets of rearranging gene segments and
have different functions.

Major Histocompatibility Complexes

any pathogen that enters the cell or is engulfed by the cell will have proteins broken
down and presented by MHC on surface of that cell which will be recognized by
respective T cell and TCR

Overview of difference between MHC class I and II

MHC class I
presents peptides of intracellular pathogens to cytotoxic T cells
activated by CD8 co-receptors
pair of lateral proteins
found in almost all cells except erythrocytes
signals apoptosis of infected cell
Molecular Structure
α1, α2, α3 domains
β2 microglobulin
not encoded in MHC gene
has grooves and pockets that only allow presentation of small peptides that are 8-10
amino acids long
MHC class II
presents peptides of extracellular pathogens to helper T cells
activated by CD4 proteins
chain of 4 protein segments
found only in macrophages, dendritic cells, and B cells
macrophages: promotes production of cytokines to activate other macrophages
and signal that there are pathogens present
B cells: signals transformation of B cells into plasma cells that can produce
specialized antibodies
Molecular Structure
α1, α2 domains
β1, β2 domains
do not have any grooves or pockets → wider space for peptides around 13-25 amino
acids long

promiscuous binding specificity → potential to bind to different peptides

distinction between self and non-self amino acids inside cells
 MHC class I: foreign proteins are loaded in endoplasmic reticulum
MHC class II: foreign proteins are loaded in endosomes

MHC Class I
Peptide-loading complex
Proteasomes
large barrel-shaped protein complex
degradation in the cytosol of proteins that are damaged, poorly folded, or no longer
needed
break down misfolded proteins and recycle peptides or amino acids for other
purposes
Immunoproteasome
In the presence of infection , cells can modify the structure of their proteasomes so
as to favor the production of peptides that bind to MHC class I molecules
induced by interferon-γ (IFN-γ) → cytokine secreted by NK cells during the
innate immune response.
modified form of the proteasome in cells exposed to IFN-γ
Constitutive proteasome
form present in the absence of infection and IFN-γ
 In all cells, proteasomes degrade cellular proteins that are poorly folded, damaged, or
unwanted. When a cell becomes infected, pathogen-derived proteins in the cytosol are
also degraded by the proteasome. Peptides are transported from the cytosol into the
lumen of the endoplasmic reticulum by the protein called transporter associated with
antigen processing (TAP), which is embedded in the endoplasmic reticulum membrane.
1. cytosolic proteins get broken down into peptide fragments by proteasomes
2. peptides pass through the TAPs into endoplasmic reticulum
TAP → transporter associated with antigen processing
3. triggers assembly of MHC class I
Calnexin
chaperone protein
attaches β2-microglobulin (β2m) to 3α domain proteins
Calreticulin & ERp57
help in peptide bonding
Tapasin
brings MHC I closer to TAP
makes it easier for foreign peptide to be loaded into MHC I
 MHC class I heavy chains assemble in the endoplasmic reticulum with the membrane-
bound protein calnexin. When this complex binds β2-microglobulin (β2m) the partly
folded MHC class I molecule is released from calnexin and then associates with the TAP
via a complex of tapasin, ERp57, and calreticulin to form the peptide-loading complex.
Degradation of cytosolic proteins by the proteasome produces some peptides (red
circles) that are delivered into the endoplasmic reticulum through TAP, and others
(black circles) that are not transported by TAP. The MHC class I molecule is retained in
the endoplasmic reticulum until it binds a peptide, which completes the folding of the
molecule. The peptide:MHC class I molecule complex is then released from the other
proteins and leaves the endoplasmic reticulum for transport to the cell surface.
Endoplasmic Reticulum Aminopeptidase (ERAP)
shortens peptides so that it may fit better in MHC class I
removes N-terminal amino acids to give a peptide of 8-10 residues
MHC Class II
found in B cells, macrophages, and dendritic cells
1. extracellular pathogen like bacteria and some protozoa will be engulfed by
macrophages or dendritic cells → enclosed in endosomes
contain enzymes that break down or inactivate proteins
2. endosomes bind to specialized vacuoles containing MHC class II

Invariant Chain
identical in all individuals
prevent MHC class II molecules from binding peptides in the endoplasmic reticulum
CLIP
class II-associated invariant chain peptide
covers binding site on MHC class II while there are no foreign peptides
HLA-DM & HLA-DO
human leukocyte antigen - DM
removes CLIP for proper loading of antigen
human leukocyte antigen - DO
retains CLIP while foreign peptide is not present

Cross-presentation
enables extracellular antigens to be presented by MHC class I
antigens located on the class II pathway of antigen presentation can be transferred to
the class I pathway of antigen presentation
When an immune response is initiated by cross-presentation this is known as cross-
priming of the immune response.
MHC Diversity
human leukocyte antigen complex
HLA I for MHC I
HLA II for MHC II
HLA diversity comes from:
MHC class II α-chains gene families
MHC class II β-chains gene families
MHC class I heavy chains gene families
genetic polymorphism
HLA-I
HLA-A, HLA-B, HLA-C
highly polymorphic
present antigen to CD8 T cells and ligands of natural killer cells
HLA-E, HLA-G
oligomorphic
present antigen to ligands of NK cells
HLA-F
monomorphic
acts as chaperone to MHC class I molecules that lose their antigen while
traveling to cell membrane
HLA-II
HLA-DP, HLA-DQ, HLA-DR
highly polymorphic
present antigen to CD4 T cells
HLA-DM, HLA-DO
oligomorphic
aids in loading onto HLA-DP, HLA-DQ, and HLA-DR
Chromosome 6

Class I region
mostly MHC-related or antigen presentation-related genes
proteins of other functions
Class II region
mostly MHC-related or antigen presentation-related genes
TAPs
tapasins
related to immunoproteasomes
Class III region
proteins not related to MHC
HLA Gene Diversity
MHC class I variability
allotype diversity in both α1 and α2 domains
β2-immunoglobulin gene comes from another chromosome (chromosome 15)
MHC class II variability
allotype diversity in either ==α1 or β1 domains ==
other domain is always non-functional
depends on MHC II isotype

MHC activation
cell signals that activate antigen presentation
interferon-α, interferon-β, interferon-γ
interferon-γ (IFN-γ)
functions in both MHC class I and II responses
MHC class I
proteasomes → immunoproteasomes
allows for breaking down of intracellular pathogens
MHC class II
activates CIITA (MHC class II transactivator)
activates MHC class II MHCs
HLA class I most likely evolved first
1. Most of HLA-II genes code for proteins strictly for antigen presentation to T cells,
while HLA I genes contain proteins with other functions
2. HLA-I related genes are found in other chromosomes
3. HLA-II is more compact compared to HLA-I
4. Some organisms such as Atlantic cod survive with only HLA-I

MHC restriction
different sides of antigen bind to MHC and T cell receptor
peptide binding sites or set of anchor residues
complementary pockets in MHC binding sites
T cell receptors also recognize residues on surface of α helices
T-cell receptor (TCR) does not recognize the same peptide when it is bound to a
different class I molecule, nor does the T-cell receptor recognize the complex with a
different peptide
MHC diversity
results from selection by infectious disease
MHC and T cell receptor diversity is dictated by natural selection
balancing selection always ensures that highly polymorphic heterozygotes are always
present

merging of populations ensures that HLA alleles are sufficiently heterozygous to

ensure survival against new diseases
meiotic recombination occurs at 2% frequency → increases with succeeding
generations
 new alleles from point mutations and recombinations
interallelic conversion or segment exchange
occurs when recombination combines segments with point mutations to
homologous segments
particularly favored seem to be new HLA alleles in which a small segment of
one allele has been replaced by the homologous section of another, with the
introduction of several amino acid substitutions that change contact residues
in the peptide-binding groove
particularly strong in the HLA-B locus in the indigenous populations of South
and Central America

Graft vs. Host Disease: Write-up Discussion

occurs during hemopoietic stem cell transplants such as bone marrow transplant
performed for patients with damaged or malfunctioning immune system or bone
marrow
recipient bone marrow is first eradicated prior to transplant
donor bone marrow contains T cells that attach the recipient tissues
Autologous
self-MHC isoforms
Allogeneic
non-self MHC isoforms
host tissues are recognized as allogeneic or different by the new T cells from the
graft
Alloreactive T Cells
alloreactive T cells will react against cells from another individual
1-10% of circulating T cells in an individual are alloreactive
HLA types
combination of HLA alleles in a person
should match in order for transplants to proceed
HLA type testing by molecular methods or HLA class I and HLA class II matching
most likely matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1
commercially-available kits
Symptoms and Side Effects
skin as most likely first organ to be affected by presence of rashes
gastrointestinal disease
diarrhea and vomiting
liver disease
hard to confirm as caused by GvHD as it has other causes
chronic GvHD
occurs after 100 days from transplant
acute GvHD
occurs prior to or within 100 days from transplant
Organ transplant rejection
recipient immune system attacks the donor organ
all cells in immune system possibly involved
can occur months after the transplant