Lucas Kemper
17.01.2011
The evolution of theadaptive immune system
Introduction
Lamprey Shark
Jawless vertebrate Jawed vertebrate
big bang
theory
conventionaladaptiveimmunity
Introduction
Lamprey Shark
What does he hasthat I don’t have?
I have:
RAG mediated rearrangingof antigen receptors
(for my B and T cells)
further mechanisms for receptor diversification
MHC molecules
(and much more)
Introduction
jawed vertebratesjaw
less
vert
ebra
tes
invertebrates
RAG mediated rearrangingof antigen receptors
further mechanisms for receptor diversification
MHC molecules
Conventional adaptiveimmunity
RAG mediated rearranging of antigen receptorsV(D)J recombination – state of the art
locus of TCR α-chain
in germline-DNA
locus ofTCR β-chain
in germline-DNA
randomly recombined DNA
randomly recombined DNA
αβ T cell receptor
RAG mediated rearranging of antigen receptorsV(D)J recombination – state of the art
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
terminal deoxynucleotidyl transferase (TdT)
germline configuration
RAG mediated rearranging of antigen receptorsV(D)J recombination – the origin of this mechanism
RAG-like transposon
Common ancestor of all jawed vertebrates
Integration in ancestral immunoglobulin gene locus*
*nature unclear*maybe innate immune receptor
first mechanismleading to variable immune receptors
excision of transposon
imprecise sealing of the gap
clonaly diverse specifities
RAG mediated rearranging of antigen receptorsV(D)J recombination – the origin of this mechanism
RAG-like transposon
Common ancestor of all jawed vertebrates
Integration in ancestral immunoglobulin gene locus*
first mechanismleading to variable immune receptors
Recombination andgene duplication
RAG location outsideof Ig and TCR loci
RSS elementsremained in
Ig and TCR locilocus duplicationtandem duplication
differentiation
Gene segments inIg and TCR loci
Further mechanisms for receptor diversification
Expansion of the potential of V D J recombination
jawed vertebrates have many
novel mechanisms and molecules
that are involved in adaptive immunity
compared with jawless fish
Lamprey Shark
Jawless vertebrate Jawed vertebrate
Further mechanisms for receptor diversification
terminal deoxynucleotidyl transferase (TdT)
germline configuration
terminal deoxynucleotidyl transferase (TdT)
lymphocyte-specific template-independent DNA polymerase
introduces untemplated nucleotides at the junctions of V, D and J segments
not found in jaweless vertebrates or below
thereby TdT increases diversity
MHC molecules
What was first?
hen or egg
rearranging αβTCR or antigen processing andpresentation by MHC
MHC molecules present antigen to αβTCR on T cells
MHC molecules
What was first?
MHC molecules present antigen to αβTCR on T cells
rearranging αβTCR or antigen processing andpresentation by MHC
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
Igs and BCR arosebefore TCR and MHC
explenatation for the developmentof an TCR-MHC system
maybe derived from phagocytosis and lysosomal processing
using VDJ recombination to recognize intracellular antigens
End of the story?
Lamprey Shark
Ha, I am so cool!But I am not helpless!
Lamprey
I can also mount anadaptive immune response
in the absence ofBCR, TCR and MHC
SharkLamprey
A convergent adaptive IS of jawless vertebratesJawless vertebrates Jawed vertebrates
A convergent adaptive IS of jawless vertebratesJawless vertebrates main features of the convergent
adaptive immune system
variable lymphocyte receptor = VLR
leucin rich repeats = LRR
generation of diversity by rearrangingLRR modules into the VLR gene
RAG-independent process
germline VLR lacks LRR modules
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 befunctionally similar to the T and B cells
jawed vertebratesjaw
les
sv
ert
eb
rate
s
invertebrates
Conclusions
BCR–TCR–MHC‑based systemis more complex
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”
jawed vertebratesjaw
les
sv
ert
eb
rate
s
invertebrates
Conclusions
BCR–TCR–MHC‑based systemis more complex
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 evolutionarypressures for adaptive immunity?
large predatory jawed vertebrateshave usualy few offsprings
adaptive immune system forhigher surival rate of offsprings?
Thank you