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TCR VDJ rearrangement question

Germlines
#1

I have a question about TCR rearrangement.

We know TCR VJD rearrangement happens in the thymus development and it’s a “somatic recombination”, dose this means TCR rearrangement only happens during the development stage of embryo development? If so, is it true that the new rearrangement will never happen again after born and the clonotype number of TCR will never increase during a human life? (decrease only?)

If there could be new VDJ recombination happens so the clonotype numbers of T cells could increase in adulthood. Is there any studies show that in what situations make the increasing of clonotype? eg, more exercise? healthy lifestyle? or any medications?

Thanks!

#2

No, in general V(D)J rearrangement happens throughout the life of the host, so any clonotype could be generated again. In mice, there are a couple of canonical BCRs/TCRs whose generation is restricted to embryonic development and that are associated with special cell populations (e.g. B1a B cells, dendritic epidermal T cells), but they are really the exception to the rule. In addition, the output of the thymus declines with age, i.e. fewer clonotypes will be generated per time interval.

#3

Thanks bussec!

what makes the regeneration of more TCRs? Just randomly rearrangement? In this case, there is no way to increase TCR clonotypes numbers, right?

#4

or it’s due to the ability of thymus?

#5

Regeneration and “more TCRs” are different things in this system:

  • Regeneration (TCR still present): Mature naive T cells undergo homeostatic proliferation, which two identical daughter cells and thus “copies” the TCR. Therefore the lifetime of the TCR in the system can be longer than the average survival time of the mature naive cell. However, in the adult animal (i.e. steady-state system) this effect is not very pronounced. The exact numbers (halflife, proliferation) should be somewhere out there.
  • Regeneration (de novo): It is in general unlikely that a “lost” TCR (i.e. previously in the host, but all cells bearing it died) is generated again. However, depending on the exact segment usage and CDR3 region, the likelihood for regeneration will range over multiple orders of magnitude.
  • more TCRs: This would mean an increase in entropy within the host. Since the mature naive T cell compartment is already close to the 1 cell per TCR limit, entropy could only be increased by having more cells in the compartment.