Cutting Edge: TCR Revision Occurs in Germinal Centers

Abstract

Mouse CD4+Vβ5+ T cells recognize a peripherally expressed superantigen encoded by an endogenous retrovirus. Ag encounter tolerizes the mature CD4 T cell compartment, either by deletion of autoreactive cells or by TCR revision. This latter process is driven by TCRβ rearrangement through RAG activity and results in the rescue of cells expressing novel TCRs that no longer recognize the tolerogen. Consistent with the notion that revising T cells represent a distinct peripheral T cell population, we now show that these lymphocyte blasts express a hybrid effector/memory phenotype and are not undergoing cell division. A population of revising T cells is CD40+, expresses the germinal center (GC) marker CXCR5, and is Vβ5lowThy-1low. Histology reveals that, consistent with their surface Ag phenotype, T cells undergoing TCR revision are enriched in splenic GCs. These data demonstrate that TCR revision is a multistep tolerance pathway supported by the unique microenvironment provided by GCs.

A Costimulatory Function for T Cell CD40

“…1 and Table I). Although the increase in CD40 ϩ cells in CIA vs control mice is modest compared with genetically predisposed autoimmune-prone strains of mice (14,17), it is consistent with the FACS profile of T cells from normal mice (9,17,67). Strains of mice that are prone to spontaneous autoimmune disease have robust expression of CD40 by T cells, whereas nondisease prone strains do not (14), so it is not surprising that C57BL/6 mice do not have as robust proportions of CD40 ϩ T cells as strains that develop autoimmune diseases relatively early in life.…”

“…Importantly, this CD40 is capable of T cell stimulation, indicating that it may have significant functional consequences (9,14,15,67). Initially, this was a surprising finding.…”

“…Strains of mice that are prone to spontaneous autoimmune disease have robust expression of CD40 by T cells, whereas nondisease prone strains do not (14), so it is not surprising that C57BL/6 mice do not have as robust proportions of CD40 ϩ T cells as strains that develop autoimmune diseases relatively early in life. A normal mouse strain can induce functional CD40 on T cells when encountering an Ag/danger signal (67), but this level still does not reach that of mouse strains prone to spontaneous autoimmune disease, which have likely been receiving chronic stimulation since early in life. However, findings presented here show that T cell CD40 can contribute to enhanced T cell activation even in individuals who do not have strong genetic predisposition to autoimmunity.…”

“…CD40 signaling leads to isotype switching and autoantibody production in B cells (90). In T cells, it has been demonstrated that CD40 engagement leads to TCR revision within germinal centers (67), skewing the T cell population further toward autoimmunity (14 -16).…”

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

“…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).…”