T cells from epicutaneously immunized mice are prone to T cell receptor revision

Yale University, New Haven, Connecticut, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2005; 102(8):2898-903. DOI: 10.1073/pnas.0409880102
Source: PubMed


Epicutaneous immunization of T cell receptor (TCR) transgenic (Tg) mice whose CD4(+) T cells are specific for the Ac1-11 fragment of myelin basic protein (MBP) with Ac1-11 elicits T cells with dominant suppressor/regulatory activity that confers protection against Ac1-11-induced experimental autoimmune encephalomyelitis. We now report that such disease-resistant MBP TCR Tg mice also harbor a sizeable fraction of peripheral CD4(+) T cells lacking surface expression of the Tg TCR beta chain and expressing diverse, endogenously rearranged TCR beta chains. Ex vivo incubation at physiological temperature caused the loss of neo-beta-chain expression and reversion to the MBP alphabeta TCR(+) phenotype. The presence of recombination activating gene 1 and 2 proteins in CD4(+) T cells with revised TCRs was consistent with effective V(D)J recombination activity. The emergence of these cells did not depend on the thymic compartment. We conclude that in mice epicutaneously immunized with an autoantigen, peripheral specific T cells are susceptible to multiple mechanisms of tolerance.

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Available from: Richard A Flavell
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    • "Furthermore, the reinduction of RAG expression that initiates TCR revision may tap into a tried and true regulatory pathway that operates during T cell development, in which TCR mediated signaling extinguishes RAG expression, while the absence of this signaling prompts its maintenance [15] [16] [17]. As such, the modulation of sTCR expression levels represents a key control point for TCR revision, and sTCR downregulation is a hallmark of this process in humans [22] [24] [25] [26] and both TCR Tg [4] [8] [10] [33] and nonTg (reference [9] and Figure 3) mice. "
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    ABSTRACT: TCR revision is a tolerance mechanism by which self-reactive TCRs expressed by mature CD4(+) peripheral T cells are replaced by receptors encoded by genes generated by post-thymic DNA rearrangement. The downmodulation of surface TCR expression initiates TCR revision, and serves as a likely trigger for the induction of the recombinase machinery. We show here in a Vβ5 transgenic mouse model system that downregulation of the self-reactive transgene-encoded TCR is not maintained by transgene loss or diminished transcription or translation. The downregulation of surface TCR expression likely occurs in two stages, only one of which requires tolerogen expression.
    Preview · Article · Nov 2011 · Cellular Immunology
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    ABSTRACT: Allelic exclusion of the murine Tcrb locus is imposed at the level of recombination and restricts each cell to produce one functional VDJbeta rearrangement. Allelic exclusion is achieved through asynchronous Vbeta to DJbeta recombination as well as feedback inhibition that terminates recombination once a functional rearrangement has occurred. Because the accessibility of Vbeta gene segment chromatin is diminished as thymocytes undergo allelic exclusion at the CD4(-)CD8(-) (double-negative) to CD4(+)CD8(+) (double-positive) transition, chromatin regulation was thought to be an important component of the feedback inhibition process. However, previous studies of chromatin regulation addressed the status of Tcrb alleles using genetic models in which both alleles remained in a germline configuration. Under physiological conditions, developing thymocytes would undergo Vbeta to DJbeta recombination on one or both alleles before the enforcement of feedback. On rearranged alleles, Vbeta gene segments that in germline configuration are regulated independently of the Tcrb enhancer are now brought into its proximity. We show in this study that in contrast to Vbeta segments on a nonrearranged allele, those situated upstream of a functionally rearranged Vbeta segment are contained in active chromatin as judged by histone H3 acetylation, histone H3 lysine 4 (K4) methylation, and germline transcription. Nevertheless, these Vbeta gene segments remain refractory to recombination in double-positive thymocytes. These results suggest that a unique feedback mechanism may operate independent of chromatin structure to inhibit Vbeta to DJbeta recombination after the double-negative stage of thymocyte development.
    Preview · Article · Nov 2005 · The Journal of Immunology
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