Unanswered Questions

How does the same weak tolerogen drive CD4+ T cells down distinct pathways leading to cell elimination, on the one hand, and cell rescue through TCR revision on the other?

No definitive experiments have yet shed light on this question, although the B cell requirement for TCR revision may be informative.20 One viable hypothesis suggests that cell death requires a strong signal delivered to a T cell, perhaps by a dendritic cell, while the signal that initiates TCR revision would be delivered by a B cell, a less potent antigen presenting cell. The exact nature of the TCR-_ chain paired with the Tg TCR-_ chain may also modulate the strength of signal delivered by a particular superantigen.37-39 In support of this argument, the TCR-_ chain repertoire of V_5 Tg mice has been shown to vary with age, becoming less diverse as V_5 expression decreases.17

How is TCR revision triggered?

If further experiments substantiate the notion that superantigens but not conventional antigens can induce reactive T cells to undergo TCR revision, it becomes important to undertand how these cellular interactions differ. The phenotype of the cells actively engaged in revision suggests that one initial trigger may be an interaction that initiates partial, but not complete, cellular activation. All work to date does suggest that one important characteristic of cells undergoing revision is their TCRlow status,20,23,24 although how this phenotype is achieved is still unclear.

Where does TCR revision take place?

The germinal center (GC) offers one potential site for TCR revision that is consistent with all available data. At this point, only CD4+ and not CD8+ T cells have been shown to undergo TCR revision.20,23,26 CD4+ T cells can enter GCs, while CD8+ T cells are excluded.40,41 TCR revision, but not cellular elimination, requires B cells20 and CD28 molecules21 both known to be required for efficient GC formation. GC T cells are activated and Thy-1low,42 as are cells undergoing TCR revision (our unpublished observations). The GC provides a niche in which B cells undergo stringent selection on the basis of their expressed antigen receptors. It is conceivable that such a selective microenvironment could impose self tolerance on a population of CD4+ T cells expressing newly generated TCRs. Using the RAG reporter mice, it should now be possible to pinpoint the location of those T cells undergoing antigen receptor revision.

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