Wednesday, 20 February 2013

T-Cell Receptors, Part Three: TCRs Where They Shoudn't Be

Wait, this isn't the right lymphocyte!

As the name implies, TCRs are receptors that you find on T cells. They're pretty well named in that regard. Seek ye TCRs, find ye T cells. Or so the story goes.

Biology is a busy, messy place, and our cells and the proteins inside them don't always behave as the textbooks might want them too. This series started out by me wanting to share some of the interesting stories I've stumbled across in my research, of TCRs popping up were perhaps we might not have expected them...

The first hints we have that perhaps the 'TC' in TCR isn't 100% accurate came not longer after the discovery of the delta chain, and in a very similar cell type. Several papers in a row show transcription of truncated, non-rearranged TCR gene transcription in B-cells, both alpha and beta chains, in normal and cancerous B-cell lines.

This perhaps isn't that surprising. B-cells are the other branch of the adaptive immune system that also produces variable antigen receptors (via V(D)J recombination). They're closely related lymphocytes, with related functions, that share an ancestry in the common lymphoid progenitor cell.

What's more, due to the shared developmental origin, somatic recombination and related purposes of the TCR and BCR loci, it's possible (if not likely) the various loci would share certain aspects of transcriptional control - the recombination machinery is certainly conserved among them.

Bearing in mind that the individual gene segments have their own promoters, and are capable of individual, non-rearranged transcription (as per the accessibility model of V(D)J recombination, where such transcription is required), it's not a huge leap to imagine that maybe B-cells just have some factors left over that drive a bit of TCR expression, of little physiological significance. The fact this story sputtered out not long after its inception might lend weight to that possibility.

The odd lymphocyte out?

I should probably mention that black sheep of the lymphocyte family, the TCR-bearing NKT cell. Now we're talking proper TCR here; rearranged genes, functional αβ heterodimers signalling on the cell surface, the whole shebang.

Discovered in 1987, these chimeric cells typically express a semi-invariant TCR, although there is a rarer, less studied type that expresses a more variable repertoire.

However, NKTs don't really have a place in this story; they're really just T-cells that went to NK cell school, so it's no surprise at all they have TCRs.

From here on in we're in much murkier territory.

The prostate examination

A little time passes before we find TCR expression popping up in new places. In 1999, while searching for highly expressed prostate genes, NIH researchers - headed by Ira Pastan - noticed an odd transcript popping up; none other than the TCRγ gene.

Oddly, it looked like the γ chain going solo; there was no δ, nor CD3, which you would have expected if the transcript was being carried in by infiltrating γδ T-cells. In situ hybridisation experiments revealed that the TCRγ transcript was being produced by acinar epithial cells.

A closer look at the transcript itself revealed that it wasn't even a full, recombined receptor gene being expressed. Instead, the sequence started with a particular TRGJ region*, which was correctly spliced onto the γ constant region.

Having done some in vitro translation on these odd γJC transcripts, they knew what size proteins they might make, if they were indeed translated in vivo. Well, fast-forward a few years and the same group is back with a vengeance. I mean antibodies, they're back with antibodies.

In their follow up paper, they show that the smaller of the two proteins encoded by the transcript (in an alternate reading frame to the typical γ transcripts we know and love) is not only expressed in the prostate, but in prostate cancer, and several breast cancer cell lines to boot. In welcoming it to the world of the translated, this protein gets a name; TCRγ alternate reading frame protein (TARP).

Over the coming few years, TARP enjoys a small but regular input of papers, showing that while involved in regulating growth, it itself is up-regulated by testosterone, via an androgen-receptor binding site in its promoter, and ends up expressed on the mitochondria.

This is pretty interesting stuff; we have (part of!) an immune receptor, being expressed in epithelial cells, under different regulation, with a different subcellular location, for presumably different purposes, but all off the same locus (which is itself within/part of the locus for another antigen receptor chain).

However, there is a whole other story that's come to dominate the TARP field in recent years; that of cancer therapeutics.

Being expressed seemingly only in healthy prostate tissues, or prostate and breast cancers, TARP makes for a pretty attractive drug target. 

One possibility is to use portions of the TARP promoter to design gene therapy vectors that will be specifically expressed in prostate tissues, allowing you to throw in a for something that (for example) inhibits cancer progression.

Closer to my own heart is the burgeoning field of TARP immunotherapeutics. Two groups have isolated CD8+ cytotoxic T-cells (CTLs) targetted against TARP peptides (HLA-A2 restricted), while another group has found some TARP-specific CD4+ T helper cells. The idea is this information could be used to possbily generate anti-TARP cancer vaccines, or T-cell therapies against established tumours.

What's more, one of the TCRs from TARP-specific CTLs has been engineered back into peripheral blood T-cells; T-cells with this TCR genetically engineered (or transduced) into them were shown to be active against HLA-A2+, TARP+ breast and prostate cancer cells, which could make for a promising treatment.

Of all the cases of wandering-TCR we see, TARP is perhaps the best appreciated and studied (I guess being a possible cure for cancer will do that). In the next two instalments in the series, we'll see some cases where the evidence is a little slimmer, or the findings perhaps a little bit more controversial, but hopefully still just as interesting.

*A note on TCR gene segment nomeclature (as defined by IMGT, whose system I use throughout my blog, along with their numbering). The first two characters represent the gene type (TR for TCR, IG for immunoglobulin), the next letter is the chain (alpha, beta, gamma, delta), and the final letter is the type of region (V, D, J or C).

On to Part 4, where we almost see TCRs where they shouldn't be 

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