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Chapter 3: Antigen
Recognition by T lymphocytes
TCR
TH1 - T Helper cell type 1
TH2 - T Helper cell type 2
TC or TCL - cytotoxic T cell
Mechanism of Self-tolerance
Positive selection = bind to self
Double selection = bind to strongly
to self
T-cell Receptor
• Two Types
1) TCR and TCR
T cells
 TCR and TCR
T cells
• Antigen Binding site
- V and V
• Similar to Fab fragment
Functions and Properties of T Cells
• T cells
- Recognize MHC:peptide complex
- Diverse Functions
A) Stimulate other immune cells
B) Cytotoxic - kill infected host cells
- Cell:cell interactions
• T cells
- Dominant T-cell in epithelial tissue
(only 1-5% in circulation)
- Recognizes more than MHC:peptide
- Not well characterized
• Antigen-Recognition
site = Peptide:MHC
Recognition site
• Single V region CDR1-3 for each chain
• All TCRs on a single T
cell are the same
• Different T cells
express different TCRs
• Diversity mechanisms
like BCRs

Figure 3-3
No Ds in Vgene
Occurs in the
Thymus
DJ first then VDJ
in gene
rearrangement

Figure
• -chain locus is
within -chain locus
3-8
• Fewer V segments
then and
• Two D segments can
be incorporated
Functional T-cell
Receptor Complex
• Core complex
• CD3 complex:  , 
• (zeta) chain
• Function of CD3 and :
Transport
Signal Transduction
Invariant Chains
Avidity
Comparison of B and T cells
PROPERTY
B CELLS
T CELLS
Bone Marrow
Thymus
Pre-antigen
Diversity
YES
YES
Post antigen
Diversity
YES
NO
Single antigen
specificity
YES
YES
Variety
Peptide:MHC
Secreted form of
Receptor
Yes
No
Invariant signaling
subunits
Yes
Yes
Initial Development
Antigen recognized
Immunodeficiency diseases
• SCID - severe combined immunodeficiency disease
- Many causes but a rare disease
- Classified according to lymphocyte profile (T B NK)
- Bone Marrow transplant can cure
• Omenn syndrome
- RAG proteins have reduced activity
- Patient is: T+ B- NK+
• CD3 and CD3 deficiency diseases
- Mutations in some CD3 genes
- Patient is: T+/TCR- B+ NK+
or T- B+ NK+
How do T cells recognize antigens?
Antigen Processing
Antigen Presentation
Antigen Presenting Cell (APC)
Professional APC
MHC class I communicates with Tc cells
MHC class II communicates with TH cells
IR to Extracellular Pathogens
(CD4-MHC II)
1. Antibodies needed
2. Pathogen recognition/internalization by
professional APCs
a. B cells
b. Macrophages
c. Dendritic cells
3. Phagolysosome degrades proteins to peptides
4. Peptides:MHC II complex transported to surface
5. Professional APC contacts CD4 T cells
6. CD4 TH cells secrete cytokines to signal B cell
maturation
IR to Intracellular Pathogens
(CD8-MHC I)
1. Antibodies ineffective
2. Pathogen replicates in the cell and proteins are
degraded in the cytoplasm of the cell
3. Peptides are transported into ER and bind MHC I
and transported to the surface
4. MHC I expressing cells present to CD8 T cells
5. CD8 T cells (cytotoxic T cell, CTL) kills host cell
Figure 3-11
Structures involved in MHC Presentation
TCR
CD4 and CD8
MHC1 and MHCII
T cell Co-Receptors
TH
Binds MHC II
TC
Binds MHC I
Figure 3-13 part 1 of 2
Variable
Invariant
CD8-MHC I
CD8-3
CD4-MHC II
CD4-2
Closed
Open
Figure 3-15
8-10 amino acids
13-25 amino acids
Degenerate binding specificity
Figure 3-16
Peptide Degradation
and Transport
Proteosome=Shredder
Transporter associated
with antigen processing
Chaperones
Calnexin
Calreticulin
Tapasin
Bare
lymphocyte
syndrome
-TAP
deficiency
-Viral
infections
Figure 3-19
Golgi Transport
Acidic process
Vacuolar Transport
Prevention of Peptide:MHC II formation in ER
CLIP - class II-associated invariant-chain peptide
Invariant Chain (li) - Prevent peptide binding in ER
- Deliver to vesicles
HLA-DM - Release of CLIP, peptide loading
TCR binds MHC and
peptide
Figure 3-21 part 2 of 3
CDR3 binds peptide
CDR2 binds MHC
CDR1a binds N-terminal
CDR1b bind C-terminal
• Cytokines
can regulate
expression
• Interferon
induces MHC
II expression
T-cell Diversity
- Recombination
- Structure of TCR and associated molecules
- Immunodeficiency diseases
Antigen Processing and Presentation
- Intracellular vs Extracellular
- MHC structure
EXTRA
Summary
INTRA
Li
Proteasome
MHC II
TAP
Golgi
Vesicle
MHC I
Golgi
Calnexin
CLIP
HLA-DM
CD4 TH
Calreticulin
Tapasin
CD8 TC
Alleles: different forms of one gene
Allotypes: different forms of one protein (isoforms)
Polymorphic: alternative forms of one gene = Many
alleles
Oligomorphic: a few forms of one gene = Few alleles
Monomorphic: no polymorphism
Homozygous: same allele on both inherited
chromosomes
Heterozygous: different allele on both inherited
chromosomes
MHC in humans is called HLA (human leukocyte
antigen complex)
Figure 3-13 part 1 of 2
Variable
Invariant
No rearrangements or somatic changes
Diversity is derived from 1) Gene families
2) Genetic polymorphism
HLA-A,B,C
-present peptide
antigens to CD8
Tcells and
interact
with NK-cells
HLA-E,G
-interact
with NK-cells
HLA-F
-?
HLA-DP,DQ,DR
- present peptide
antigens to CD4
Tcells
HLA-DM,DO
-regulate peptide
loading of
DP,DQ,DR
Human leukocyte antigen complex
Abs used to ID MHC molecules react with leukocytes not RBCs
Figure 3-24 part 1 of 2

Heavy Chain

Heavy Chains
Chromosome Organization of HLA complex
Chr6
2-microglobulin on chr15
•  and  chain = GeneA and GeneB
• Haplotype - combination of alleles inherited from Chr6
• 2% meiotic recombination rate generates population diversity
•Crossover: Haplotypes, normally, are inherited intact and hence antigens
encoded by different loci are inherited together (e.g., A2; B27; Cw2; DPw6;
DQw9; DRw2). However, on occasions, there is crossing over between two
parental chromosomes resulting in new recombinant haplotypes. Thus, any
one specificity encoded by one locus may combine with specificities from
other loci. This results in vast heterogeneity in the MHC make-up in a given
population.
• Cytokines (Interferons) coordinately regulate the group of
genes - class I heavy chain and other associated genes
• TAP transporter, Tapasin, Proteasome subunits - LMP2 and
LMP7 ---> all proteins involved in Antigen Processing
Interferon , , and  ----> Class I , 2M, TAP, LMP2, LMP7
HLA II
Interferon  ----> CIITA transcription factor ---> genes, li
chain
MHC class II transactivator (CIITA) - deficiency leads
to bare lymphocyte syndrome
MHC I (single peptide binding chain ): 3 genes to
present antigen
HLA-A, HLA-B, HLA-C
MHC II (two chains,  and ): 3 genesb to present
antigen
HLA-DQ, HLA-DP, HLA-DR
Each MHC II locus encodes a gene for the  chain
and a gene for the  chain:
e.g. HLA-DQA, HLA-DQB => MHC II isoforms
HLA-DPA, HLA-DPB => MHC II isoforms
HLA-DRA, HLA-DRB => MHC II isoforms
Maternal: 3 MHC I genes
HLA-AM, HLA-BM, HLA-CM
Paternal: 3 MHC I genes
HLA-AP, HLA-BP, HLA-CP
6 different MHC I
proteins on all cells
Heterozygous
Maternal: 3 MHC II genes
HLA-DPAM, HLA-DPBM
HLA-DQAM, HLA-DQBM
HLA-DRAM, HLA-DRBM
Paternal: 3 MHC II genes
HLA-DPAP, HLA-DPBP
HLA-DQAP, HLA-DQBP
HLA-DRAP, HLA-DRBP
6 different MHC II
proteins on all cells
(some individuals
have 8 due to two
HLA-DRB genes)
Homozygous = one DR type
Heterozygous = up to four
DR combinations, but only
3 types can be made by one
person
HLA-DRAP, HLA-DRB1P
HLA-DRAP, HLA-DRB3P
HLA-DRAP, HLA-DRB4P
Figure
Correlation is mainly
with HLA class I 3-34consistent with killing
of virus infected cells
Red – heterozygous for all the highly polymorphic HLA I & II
Yellow - Homozygous for one locus
Blue - Homozygous for two or three loci
Seroconversion - when antibodies have first been detected
Figure 3-28 part 1 of 2
MHC
One MHC isoform can bind multiple peptides
Contact residues - the MHC amino acid residues that interact
with TCR or the bound peptide
Figure 3-28 part 2 of 2
 chain
HLA-DR
 chain
Error in the textbook on HLA-DR (oligomorphic vs invariant)
Figure 3-29
Anchor residues (green) - peptide amino acids interacting with
MHC
Peptide binding motif - combination of anchor residues
Figure 3-30
Co-
MHC restriction - TCR recognizes the complex of
both the peptide and MHC by interacting with
exposed amino acid residues
Balancing Selection
Favors multiple alleles
Large circles- totalFigure
#
antigenic
peptides that can be
presented
via MHCI & MHCII
small circles- total #
antigenic
peptides that can be
presented
via an individual
MHCI & MHCII haplotype
3-31
Advantages for heterozygous for the MHC
Figure 3-32 part 1 of 2
Figure 3-32 part 2 of 2
Different mechanism
from recombination DNA is exchanged
between alleles and
copied in one
direction to
generation new MHC
allele
HLA B*5301Found in African
populations and
associated with
resistance to severe
malaria
Figure 3-33 part 2 of 2
Recombination between
alleles of a different
gene
Generation of new
MHC alleles
HLA B*4601- Found in southeast Asian
populations and
associated with susceptibility to
nasopharyngeal carcinoma.
MHC selection by Infectious Disease
• Pathogens adapt to avoid MHC - recent MHC isoform may
provide a survival advantage (hence higher frequency level)
• Epidemic diseases place survival advantages on those who
can best present pathogenic peptides
• Only a minority of HLA alleles are common to all humans
- most are recent and specific to ethnic groups
HLA Type and Disease Susceptibility
Ankylosing spondylitis
IDDM
Multiple Sclerosis
Narcolepsy
Rheumatoid arthritis
Lupus (SLE)
AIDS (rapid)
AIDS (slow)
B27
DR4/DR3
DR2
DR2
DR4
DR3
HLA-A29, HLA-B22
HLA-C16, HLA-DR11
HLA-B14, B27, B57
HLA-C8, C14
MHC polymorphism and Organ Transplants
• Developing T cells that recognize complexes of
peptide and MHC molecules on HEALTHY tissue (selfpeptides presented by self MHC) are DESTROYED
• This results in the preservation of T cells that
recognize non-self MHC (allogeneic MHC). These are
alloreactive T cells and are 1-10% of total T-cell
repertoire
• Immune system is primed for rejection of foreign
organs that express allogeneic MHC
• THIS IS WHY YOU WANT TO MATCH HLA TYPE