The number of T-helper subsets is staggering. Well, staggering compared to the initial See-Saw* relationship we envisioned existing between the Th1 and Th2 profiles. A lot is known about these subsets, their hallmark cytokines, the transcription factors they couple with, and what musical genres really get them in a mood for proliferation…not really.
What is not known, however, shockingly, is what exactly initiates signaling at the T-cell Receptor (TCR)? Weird, isn’t it? We got so caught up with all the drama in the middle of the story that we never bothered to ask how the story began?
The TCR is as elegantly put together and enigmatic as Don Draper. It is a membrane-spanning heterodimer made up of an elaborate, two-layered bow-tie of β-pleated sheets: the classical immunoglobulin fold, as it were. The variable regions of this heterodimer, the Vα and the Vβ, interact via their bottom β-sheets. The constant regions also conform to the immunoglobulin fold but with one distinction: the top-most β-sheet of the Cα region is replaced by two linker-like strands. The significance of this pocket is not known. Yet. The extra-cellular domain of the TCR has the aspect of the antigen-binding fragment (or Fab) region of an antibody molecule. That the extracellular domain of the TCR is what sidles up to the edges of a peptide-loaded MHC (pMHC) molecule to sample said peptide, this structural feature, so adept at recognition, makes a world of sense.
A co-conspirator of the TCR is CD3. Or rather, the four polypeptide chains(ε, γ, δ and ε) that make up CD3. Sort of the Roger Sterling to the TCR’s Don Draper, the intra-cellular regions of CD3 bear Immunoreceptor Tyrosine-based Activation Motifs (ITAMs), the phosphorylation of which is one of early moments of signal transduction that activates a T-cell. In a lovingly rendered and thoroughly detailed treatment of how the TCR and CD3 fit together, Dr. Mike Kuhns of the University of Arizona (whom I’ve had the pleasure of dining with!) describes how the CD3δε and the CD3γε, in an “open face orientation”, dock on either side of the TCR. This not only provides evidence for there being sidedness for the TCR-CD3 complex, but also that the clustering of the complexes isn’t a random pile-up of multimeric complexes that orgiastically make signalling happen.
Ah, yes, the clustering! So much contention with the clustering. Are the TCR-CD3 clusters pre-assembled or do they huddle together once the TCR is activated? But as Xie et al tell us, in the T-cell’s self-communion, LAT (Linker of Activated T-cells) and TCR microclusters just lurk beneath the cell surface membrane, ready to co-mingle with CD3 when the time is right, and migrate to what becomes the inner circle of the cluster of receptors on the cell-surface: the central supramolecular activation cluster (cSMAC). The TCRs of the cSMAC are, themselves, bedizen with a cluster of accessory molecules like LFA-1 which form the peripheral SMAC or the pSMAC. In a conversation between antigen presenting cells and T-cells: these interactions ask the rather pivotal question of, “Shall we dance?” If the answer is “We shall!”, we might see some cytokine action!
Take care now,