Differential Regulation of Peripheral CD4+ T Cell Tolerance Induced by Deletion and TCR Revision

Abstract

In Vβ5 transgenic mice, mature Vβ5+CD4+ T cells are tolerized upon recognition of a self Ag, encoded by a defective endogenous retrovirus, whose expression is confined to the lymphoid periphery. Cells are driven by the tolerogen to enter one of two tolerance pathways, deletion or TCR revision. CD4+ T cells entering the former pathway are rendered anergic and then eliminated. In contrast, TCR revision drives gene rearrangement at the endogenous TCR β locus and results in the appearance of Vβ5−, endogenous Vβ+, CD4+ T cells that are both self-tolerant and functional. An analysis of the molecules that influence each of these pathways was conducted to understand better the nature of the interactions that control tolerance induction in the lymphoid periphery. These studies reveal that deletion is efficient in reconstituted radiation chimeras and is B cell, CD28, inducible costimulatory molecule, Fas, CD4, and CD8 independent. In contrast, TCR revision is radiosensitive, B cell, CD28, and inducible costimulatory molecule dependent, Fas and CD4 influenced, and CD8 independent. Our data demonstrate the differential regulation of these two divergent tolerance pathways, despite the fact that they are both driven by the same tolerogen and restricted to mature CD4+ T cells.

Cutting Edge: TCR Revision Occurs in Germinal Centers

“…One hypothesis to explain how Mtv-8-experienced T cells enter one pathway vs the other suggests that when V␤5 ϩ CD4 ϩ T cells encounter Mtv-8, some receive a weak or partial signal that induces the TCR revision pathway and some perceive a stronger Mtv-8 signal and are thereby deleted (16). In line with this hypothesis, TCR revision requires B cells and CD28 and ICOS molecules and is enhanced in the absence of functional Fas molecules, while the deletional pathway is B cell, CD28, Fas, and ICOS independent (3,4,17). Although these data hint that Mtv-8 expression by distinct cell types may deliver signals that instruct the partner T cell to die or to revise, little is known either about what triggers TCR revision or its mechanistic details.…”

“…Because GCs potentiate the selection of B cells on the basis of their expressed Ag receptors, these microenvironments could also provide niches for imposing self-tolerance on T cell populations expressing newly generated TCRs. In support of this notion, TCR revision in our system (4,17,25) is restricted to CD4 ϩ T cells (as is entry into GCs) and is dependent on B cells and CD28 expression (as is GC formation). We now show (Fig.…”

Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions

“…Given that revision generates a functional and self-tolerant TCR, the revising T cell is likely subjected to some form of selection. Indeed, the frequency of revising T cells is increased in the absence of the proapoptotic molecule Bcl-2-interacting mediator of cell death (26), and the accumulation of postrevision T cells is enhanced in the absence of the death receptor Fas (27). These results suggest that apoptosis plays a role in the selection of the postrevision T-cell repertoire.…”

“…with this notion, TCR revision in most models excludes CD8 T cells (3) and, unlike deletion, requires B cells, inducible T-cell costimulator (ICOS), and CD28 (27). In addition, immunohistochemistry of revising T cells, identified in Rag2p-GFP Tg mice in which GFP is expressed under the control of the Rag2 promoter (22), suggests that revising T cells localize predominantly in or near splenic GCs (31).…”

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

“…Hence, the corpus of data supports the occurrence of RAG-mediated receptor revision in CD4 ϩ V␤8.2 Ϫ T cells from disease-resistant mice. Such a TCR revision phenomenon (27) among peripheral T cells was perhaps best characterized by studying the fate of Tg CD4 ϩ V␤5 ϩ T cells exposed in vivo to a mouse mammary tumor virus 8-encoded peripheral superantigen (20,(28)(29)(30)(31). In our system, maintenance of TCR revision appeared to require factor(s) present in vivo, because acquisition of the 3H12 ϩ phenotype occurred relatively rapidly ex vivo.…”