Transcript RAG mediated rearranging of antigen receptors

The evolution of the
adaptive immune system
Lucas Kemper
17.01.2011
Introduction
Lamprey
Shark
big bang
theory
Jawless vertebrate
conventional
adaptive
immunity
Jawed vertebrate
Introduction
Lamprey
Shark
I have:
What does he has
that I don’t have?
RAG mediated rearranging
of antigen receptors
(for my B and T cells)
further mechanisms for
receptor diversification
MHC molecules
(and much more)
invertebrates
jawless
vertebrates
Introduction
jawed vertebrates
Conventional adaptive
immunity
RAG mediated rearranging
of antigen receptors
further mechanisms for
receptor diversification
MHC molecules
RAG mediated rearranging of antigen receptors
V(D)J recombination – state of the art
locus of
TCR α-chain
in germline-DNA
randomly recombined DNA
αβ T cell receptor
randomly recombined DNA
locus of
TCR β-chain
in germline-DNA
RAG mediated rearranging of antigen receptors
V(D)J recombination – state of the art
germline configuration
terminal deoxynucleotidyl
transferase (TdT)
RAG complex binds recombination signal sequence
RAG complexes arrange next to each other
RAG complex cleaves DNA and hairpins are formed
Endonucleases open the hairpin randomly
Random nucleotides are added by TdT and/or deleted by endonucleases
Ligation of DNA
RAG mediated rearranging of antigen receptors
V(D)J recombination – the origin of this mechanism
RAG-like transposon
first mechanism
leading to variable
immune receptors
 excision of transposon
Common ancestor
of all jawed vertebrates
 imprecise sealing
of the gap
 clonaly diverse specifities
Integration in ancestral
immunoglobulin gene locus*
*nature unclear
*maybe innate immune receptor
RAG mediated rearranging of antigen receptors
V(D)J recombination – the origin of this mechanism
first mechanism
leading to variable
immune receptors
RAG-like transposon
Common ancestor
of all jawed vertebrates
Integration in ancestral
immunoglobulin gene locus*
Gene segments in
Ig and TCR loci
differentiation
Recombination and
gene duplication
RAG location outside
of Ig and TCR loci
locus duplication
tandem duplication
RSS elements
remained in
Ig and TCR loci
Further mechanisms for receptor diversification
jawed vertebrates have many
Lamprey
Shark
novel mechanisms and molecules
that are involved in adaptive immunity
compared with jawless fish
Jawless vertebrate
Jawed vertebrate
Expansion of the potential of V D J recombination
Further mechanisms for receptor diversification
germline configuration
terminal deoxynucleotidyl
transferase (TdT)
terminal deoxynucleotidyl transferase (TdT)
lymphocyte-specific template-independent DNA polymerase
introduces untemplated nucleotides at the junctions of V, D and J segments
thereby TdT increases diversity
not found in jaweless vertebrates or below
MHC molecules
MHC molecules present antigen to αβTCR on T cells
What was first?
hen
or
egg
rearranging αβTCR
or
antigen processing and
presentation by MHC
MHC molecules
MHC molecules present antigen to αβTCR on T cells
What was first?
αβTCR and MHC appeared at the same time in evolution
no αβTCR and MHC outside of jawed vertebrates
therefore it is difficult to answer what was first
rearranging αβTCR
Igs and BCR arose
before TCR and MHC
or
antigen processing and
explenatation for the development
presentation by MHC
of an TCR-MHC system
 maybe derived from phagocytosis
and lysosomal processing
 using VDJ recombination to
recognize intracellular antigens
End of the story?
Lamprey
But I am not helpless!
I can also mount an
adaptive immune response
in the absence of
BCR, TCR and MHC
Shark
Ha, I am so cool!
A convergent adaptive IS of jawless vertebrates
Jawless vertebrates
Lamprey
Jawed
Sharkvertebrates
A convergent adaptive IS of jawless vertebrates
Jawless vertebrates
main features of the convergent
adaptive immune system
germline VLR lacks LRR modules
generation of diversity by rearranging
LRR modules into the VLR gene
RAG-independent process
a single VLR gene can have combinatorial
diversity comparable to that of Igs
Two VLR genes known
(membrane-bound and secreted)
two populations of lymphoid cells that seem to be
functionally similar to the T and B cells
variable lymphocyte receptor = VLR
leucin rich repeats = LRR
Conclusions
jawless and jawed fish both have an AIS
based on different gene families
RAG transposon had major role in the
emergence of the jawed vertebrate AIS
What about the big bang theory?
Still holds true for conventional
adaptive immunity
(BCR, TCR, MHC)
but
“could be more a set of observations
made from a limited phylogenetic
sampling and mechanistic focus than a
true representation of rapid evolution”
invertebrates
jawless
vertebrates
BCR–TCR–MHC-based system
is more complex
jawed vertebrates
Conclusions
jawless and jawed fish both have an AIS
based on different gene families
RAG transposon had major role in the
emergence of the jawed vertebrate AIS
What about the evolutionary
pressures for adaptive immunity?
large predatory jawed vertebrates
have usualy few offsprings
adaptive immune system for
higher surival rate of offsprings?
invertebrates
jawless
vertebrates
BCR–TCR–MHC-based system
is more complex
jawed vertebrates
Thank you