Cognate CD4+ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8+ T Cells

Abstract

Peripheral tolerance is required to prevent autoimmune tissue destruction by self-reactive T cells that escape negative selection in the thymus. One mechanism of peripheral tolerance in CD8+ T cells is their activation by resting dendritic cells (DC). In contrast, DC can be “licensed” by CD4+ T cells to induce cytotoxic function in CD8+ T cells. The question that then arises, whether CD4+ T cell help could impair peripheral tolerance induction in self-reactive CD8+ T cells, has not been addressed. In this study we show that CD4+ T cell activation by resting DC results in helper function that transiently promotes the expansion and differentiation of cognate CD8+ T cells. However, both the CD4+ and CD8+ T cell populations ultimately undergo partial deletion and acquire Ag unresponsiveness, disabling their ability to destroy OVA-expressing pancreatic β cells and cause diabetes. Thus, effective peripheral tolerance can be induced by resting DC in the presence of CD4+ and CD8+ T cells with specificity for the same Ag.

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

“…In contrast, activated and memory CD4 1 T cells could provide activation signals to DC through, for instance, CD40/ CD40L interactions [41] and promote DC activation [42][43][44] thereby limiting the ability of the DC to induce peripheral tolerance. Indeed, we and others have shown previously that coactivation of cognate CD4 1 T-cell help impairs tolerance induction, but for antigen transgenically targeted to DC this effect is transient [13]. While here, we did not specifically examine whether memory CD4 1 T cells activated cognate antigenexpressing DC, our data demonstrate that tolerance induction is not prevented.…”

“…Previous studies examining the response of naïve CD4 1 T cells to tolerogenic antigen presentation, regardless of whether antigen was targeted to DC or not, have almost universally demonstrated major contributions from both deletion and induction of unresponsiveness in the residual, nondeleted, population [13,27]. This study indicates that, for CD4 1 memory T cells, deletion may be a key mechanism of tolerance induction as few residual OT-II cells are seen at any site tested.…”

“…As the CD11c promoter appears to drive low-level transgene expression in CD11c int cells [16], which includes plasmacytoid DC, some activated macrophages, subsets of intraepithelial lymphocytes and NK1.1 1 cells, we previously showed that the presentation of immunogenic MHC/OVA peptide complexes was restricted to CD11c hi conventional DC [13]. Additionally, Taqman qPCR studies have shown OVA message is restricted to DC and not expressed in B and T cells of 11c.OVA mice [15].…”

“…OT-II mice carrying a transgenic TCR specific for I-A b /OVA 323-339 [45] were crossed with CD45.1 congenic C57BL/6.SJL-Ptprc a mice to generate mice bearing CD45.1 1 OT-II cells. 11c.OVA mice express a membrane-bound OVA construct under the control of the CD11c promoter, which targets OVA expression to CD11c hi conventional DC [13]. Mice were sex matched within experiments and used at 8-12 wk of age.…”

“…No Foxp3 expression was detected in CD4 1 T cells recovered from these cultures (data not shown). Therefore, we conclude that these culture conditions generate a population of OT-II T cells phenotypically similar to central memory T cells and skewed toward a Th1 phenotype.OVA-specific memory CD4 1 T cells are activated upon transfer to mice expressing OVA in DC Using a model in which OVA expression is targeted to DC by the CD11c promoter, we have shown that steady-state presentation of OVA by OVA-expressing DC induces peripheral tolerance in naïve CD4 1 and CD8 1 T cells [13,14] and memory and effector CD8 1 T cells [4,15]. As the CD11c promoter appears to drive low-level transgene expression in CD11c int cells [16], which includes plasmacytoid DC, some activated macrophages, subsets of intraepithelial lymphocytes and NK1.1 1 cells, we previously showed that the presentation of immunogenic MHC/OVA peptide complexes was restricted to CD11c hi conventional DC [13].…”