Archive for June, 2009

Memory T cells

Alert to journal editors, especially in immunology/signal transduction:

There have been three high-profile papers on signal transduction pathways affecting memory T cells recently.

We have the metformin paper in Nature from Choi’s group at Penn. The mTOR rapamycin paper from Ahmed + Larsen at Emory. And the Wnt paper in Nature Medicine from NIH.

And how about sphingosine-1-phosphate?

Aren’t these all different facets of the same thing?

Amazingly, there was just a piece in Nature Reviews Immunology on “Immunoregulatory functions of mTOR inhibition” that only says this at the end: “Insight is also needed into the role of mTOR in memory.”

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Lampreys

A recent paper from Max Cooper’s lab at Emory has provided an example of an alternative path for evolution, one that disturbs and complicates our picture of how the immune system might have evolved.

Like discovering a place where everyone drives steam turbine-driven cars. Makes me think about Stephen Jay Gould and how evolution doesn’t always have a defined direction leading up to humans.

A review: the cut-and-error-prone-paste process of V(D)J recombination, which assembles antibody genes, seems to have jumped into the early vertebrate genome hundreds of millions of years ago.

When and how did this happen? John Travis’ essay makes the point that recently this process is looking less like a “big bang” and more gradual. But then came the lampreys.

T cells and B cells are two arms of the immune system that resemble each other. One responds to peptides displayed by MHC, a useful tool for fighting viruses inside our cells. The other makes antibodies that bind to antigens and can secrete the antibodies, which are great for clearing nasty pathogens from the blood.

Both have receptors on their surfaces that get rearranged by V(D)J, and the genes look similar. One possible order of events is this: there was a primordial “antigen receptor” bearing cell. V(D)J invades the genome, then this primordial cells splits off into T and B.

But no! Lampreys have cells that look like T and B, without V(D)J or the genes that make it possible, RAG1 and RAG2. One set of cells make secreted “variable lymphocyte receptors” and the other doesn’t. One looks like T and the other looks like B, judging from the genes they express.

Lampreys use another genetic shuffling tool to assemble their VLR genes – looks like gene conversion.

It’s worth pointing out that mice and people get most of their immunological diversity from V(D)J but rabbits and chickens don’t, using gene conversion/hypermutation (a process that may have predated V(D)J).

So it looks like the distinction between T and B may have existed first, before V(D)J complicated matters.

Still puzzling is the apparent absence of MHC and a thymus in lampreys, so what T cells respond to and where they develop in lampreys is unclear.

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Evolution of VDJ

Our immune systems have the impressive ability to handle a wide variety of nasty bugs, but when you look “under the hood” at the genes involved, it can look like a Rube Goldberg machine.
Antibody genes get taken apart and put back together in a semi-random way that generates a vast armory of tools, all varying slightly from each other. This process, known as V(D)J recombination, generates the diversity (many genetically different cells within one person!) necessary to respond to what nature throws at us.
It’s hard to believe that a process like this could emerge bit by bit through evolution, but the immune system was actually a centerpiece of the 2005 Kitzmiller v. Dover trial, where a Pennsylviania school district’s requirement to teach “intelligent design” was successfully challenged.
John Travis, as part of a series of essays celebrating Charles Darwin’s life and work in Science, describes this in greater detail. He lays out how scientists have gradually built their understanding of how V(D)J recombination may have been at first “planted” in animals’ immune systems and blossomed later on.

By the way, one of the papers that emerged from my time in David Schatz‘s lab is on the evidence list for the trial! I was thrilled to discover this even several years later. My fellow graduate student Alka Agrawal was first author of the paper. She went on to win a prize for an essay explaining the significance of our work.

RAG-mediated transposition and a model for the origins of split antigen receptor genes. (A) Possible structure of the original transposable element that integrated into the germ line of an ancestral vertebrate. Dashed arrows indicate the direction of transcription of the RAG1 and RAG2 genes. (B) The current "split" nature of immunoglobulin and T cell receptor genes is proposed to have arisen from RAG-mediated transposition of one or two excised elements into a primordial receptor gene exon (dark green), thereby dividing the exon into two or three gene segments, each flanked by one or two recombination signals (black and white triangles). These gene segments would represent the evolutionary precursors of current V, D, and J gene segments. Different patterns of gene duplication (right) would result in the "mammalian" or "cluster" configurations of gene segments characteristic of the heavy-chain locus of mammals or cartilaginous fishes, respectively. The constant region exons (C) are represented as a single gray rectangle.

RAG-mediated transposition and a model for the origins of split antigen receptor genes. (A) Possible structure of the original transposable element that integrated into the germ line of an ancestral vertebrate. Dashed arrows indicate the direction of transcription of the RAG1 and RAG2 genes. (B) The current "split" nature of immunoglobulin and T cell receptor genes is proposed to have arisen from RAG-mediated transposition of one or two excised elements into a primordial receptor gene exon (dark green), thereby dividing the exon into two or three gene segments, each flanked by one or two recombination signals (black and white triangles). These gene segments would represent the evolutionary precursors of current V, D, and J gene segments. Different patterns of gene duplication (right) would result in the "mammalian" or "cluster" configurations of gene segments characteristic of the heavy-chain locus of mammals or cartilaginous fishes, respectively. The constant region exons (C) are represented as a single gray rectangle.

Travis points out that more recently, scientists have found that enzymes resembling RAG1 and RAG2, the “scissors” that cut the DNA to initiate V(D)J, have been found in sea urchins (ie before vertebrates emerged), and it’s not clear what they do there.

Travis writes:

Their existence in the urchin suggests that the transposon [jumping DNA] with these enzymes invaded animals far earlier than had been thought but was lost in most lineages except for jawed vertebrates, which adapted them to perform VDJ recombination. That’s an easier version of the story for some immunologists to swallow, as it allows more time for mutations to deactivate the jumping ability of a transposon and convert its DNA to a new job.

Clearly, our picture of how VDJ evolved will continue to change as more genomic/wet biological information becomes available for species close to the vertebrate/invertebrate line, like lampreys. That leads me to my next post…

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