Antibodies and T Cell Receptor
Genetics
2011
Peter Burrows
4-6529
406 Shelby
peterb@uab.edu
Antibodies and T Cell Receptor Genetics
Learning Objectives
• To understand mechanisms for creating
diversity
– Be able to identify changes at the DNA
level required to produce a functional
immunoglobulin gene
• To understand isotype switching at the
molecular level
• To recognize basic differences between
antigen receptors on B and T cells
Generation of Antigen Receptor
Diversity
• Survival requires B and T cell receptor
diversity to respond to the diversity
of pathogens
• The immune system must “Be
Prepared” to respond to antigens it
has never encountered
• One to 100 million different antigen
receptors (Ig on B cells, TCR on T
cells) can be produced
Generation of Diversity
Cellular Solutions
• Diversity operates at the level of the
lymphocyte
• Each lymphocyte has a unique receptor for
antigen
• Produce one million different lymphocytes per
day
• Antigen selects cells by binding to a
complementary receptor and stimulating cell
division and differentiation (antibodysecreting plasma cells or effector T cells)
Antigen Selects Lymphocytes
Isotype
Switch
IgG, IgA, IgE
Isotype
Switch
IgG, IgA, IgE
Antigen-Antibody Binding
Generation of Diversity
• Survival requires diversity to respond
to the diversity of pathogens
• One to 100 million different
antibodies can be produced
• Nine isotypes
• Similar numbers of T cell receptors
for antigen
Problem - Not enough DNA to support observed diversity
10 x 106 genes X 103 base pairs DNA/gene = 10 x 109 bp
> 3 X 109 bp DNA available
Anatomy of a typical gene
Inside the cell
Cell membrane
Outside the cell
Anatomy of Immunoglobulin
Genes in B Lymphocytes
Intron
V Region C Region
Exon
Exon
DNA
mRNA
Protein
Generation of Diversity
Genetic Solutions
• Functional genes for antigen receptors do
not exist until they are generated during
the development of lymphocytes
• Variable region exons are formed by
splicing together segments of genes
inherited through the germline
• The process is called Ig or TCR gene
rearrangement, and generates tremendous
diversity without monopolizing the genome
Variable region genes are constructed from
gene segments
Germline
DNA
Stem cell
B Cell
DNA
mRNA
Protein
Germline Ig Genes
V-region Gene Segments are Joined
by Somatic Recombination
Germline
DNA
Stem cell
B Cell
DNA
mRNA
Protein
Somatic recombination at the Ig heavy chain locus
*
*
*
Germline DNA
D  JH rearrangement
V  DJH rearrangement
Primary RNA transcript
Splicing and polyA  mRNA
Nascent polypeptide
Mature μ heavy chain protein
Benefits of Antigen Receptor Gene
Rearrangement
40 Vκ
x 5 Jκ
200 κ V regions
30 Vλ
x 3 Jλ
65 VH
27 DH
x 6 JH
90 λ V regions 10,530 H V regions
How many antibodies can be made?
(10,530 HC) x (200 κ LC) = 2.1 x 106 IgM κ antibodies
(10,530 HC) x (90 λ LC) = 0.9 x 106 IgM λ antibodies
3 million total
Not bad from 176 gene segments!
One B cell or plasma cell only makes one antibody
Isotype Switching Also Occurs by
Somatic Recombination
VL
VH
IgM B Cell
VH
VL
Isotype Switching Also Occurs by
Somatic Recombination
Switch Recombination
Advantage No requirement for separate VDJH
recombination for each isotype
Only cells that switch will be those
responding to antigen
Features Irreversible
Individual plasma cell produces
one isotype
one specificity
Primary and Secondary Antibody
Responses
Primary
Secondary
Higher titer
Higher affinity
© 1998 Gold Standard Multimedia Inc.
The T Cell Receptor for Antigen
TCR
Comparison of the TCR and the BCR
(Immunoglobulin)
V regions
encoded by
rearranging
genes
Structure of the T-cell Receptor
The T Cell Receptor
• Heterodimer that only exists as a
transmembrane antigen receptor
• It is not secreted since T cells function by
direct cell contact
• The variable regions of the TCR are
generated by somatic gene recombination as
the T cells develop in the Thymus
• The process is identical to Ig gene
rearrangement, but different genes are used
T-cell Receptor - and -chain V Regions are
Generated by Gene Segment Rearrangement
B cells recognize intact protein antigens
Heavy Chain
Lysozyme
Antigenic Determinant
Light Chain
Epitope
T cells recognize processed (degraded)
protein antigens
Dangers in Diversity
• Mechanism is essentially a random
draw
• By chance, some Ig and TCR will
react with self antigens
• Autoreactive B and T cells must be
eliminated or silenced to prevent
autoimmune diseases
• Chromosomal translocations arising
during VDJ recombination or isotype
switching may lead to lymphoid
malignancies
NJEM