The majority of T cells from young mice carrying a functionally rearranged TCR-p chain transgene express that gene, constituting a population of T cells expressing diverse TCR-a chains paired with a uniform, transgene-encoded TCR-p chain.15 In Vp5 transgenic (Tg) mice, transgene expression among CD8-T cells remains high at all ages. However, Vp5 expression among CD4+ peripheral T cells decreases with age, and concomitantly, expression of TCR-p chains encoded by rearranged endogenous genes increases.16 The lymphoid periphery of Vp5 Tg mice is also characterized by a striking age-dependent inversion of the CD4:CD8 ratio. Both the inversion of the CD4:CD8 ratio (caused by the loss of CD4+ peripheral T cells) and the loss of transgene expression (caused by the appearance of cells expressing endogenous Vps or Vpendo) are dependent on a superantigen encoded by a defective endogenous mammary tumor virus (Mtv)-8.17 Expression of the

Mtv-8-encoded superantigen appears to be confined to the lymphoid periphery, and provides for an unusually weak interaction with Vp5+ TCRs.18

The interaction between Vp5+CD4+ T cells and MHC class II+Mtv-8+ cells drives the T cell partner down one of two tolerance pathways (Fig. E2.1). The CD4+ T cell can be rendered anergic and die, thereby effecting an inversion of the CD4:CD8 ratio, or it can be rescued by losing Mtv-8 reactivity upon extinction of Vp5 surface expression. This latter pathway is called TCR revision because the loss of Vp5 surface expression occurs hand-in-hand with the acquisition of endogenously-derived TCR-p chains.19 T cells from Vp5 Tg mice do not undergo TCR revision in the absence of either B cells or CD28 molecules,20,21 and revision appears to be highly inefficient in lethally irradiated Mtv-8+ hosts whose hematopoietic systems have been reconstituted with bone marrow from Mtv-8+ donors (McMahan CJ, Fink PJ, unpublished observations). In contrast, the deletional pathway is fully operative in Vp5 Tg mice lacking B cells or CD28 molecules, and after lethal irradiation and bone marrow reconstitution. Thus, encounter with the same weak tolerogen can drive CD4+ T cells down alternate pathways leading to cell deletion or cell rescue through TCR revision.

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