Conversion of effector CD4^(+)T cells to a CD8^(+)MHC Ⅱ-recognizing lineage

CD4^(+)and CD8^(+)T cells are dichotomous lineages in adaptive immunity.While conventionally viewed as distinct fates that are fixed after thymic development,accumulating evidence indicates that these two populations can exhibit significant lineage plasticity,particularly upon TCR-mediated activation.We define a novel CD4^(-)CD8αβ^(+)MHC Ⅱ-recognizing population generated by lineage conversion from effector CD4^(+)T cells.CD4-CD8αβ^(+)effector T cells downregulated the expression of T helper cell-associated costimulatory molecules and inaeased the expression of cytotoxic T lymphocyte-associated cytotoxic molecules.This shift in functional potential corresponded with a CD8^(+)-lineage skewed transcriptional profile.TCRβ repertoire sequencing and in vivo genetic lineage tracing in acutely infected wild-type mice demonstrated that CD4^(-)CD8αβ^(+)effector T cells arise from fundamental lineage reprogramming of bona fide effector CD4^(+)T cells.Impairing autophagy via functional deletion of the initiating kinase Vps34 or the downstream enzyme Atg7 enhanced the generation of this cell population.These findings suggest that effector CD4^(+)T cells can exhibit a previously unreported degree of skewing towards the CD8^(+)T cell lineage,which may point towards a novel direction for HIV vaccine design.

CD98-induced CD147 signaling stabilizes the Foxp3 protein to maintain tissue homeostasis

Regulatory T cell(Treg)stability is necessary for the proper control of immune activity and tissue homeostasis.However,it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions.Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability.Here,we demonstrate that to maintain Foxp3 protein expression,Tregs require cell-to-cell contact,which is mediated by the CD147-CD98 interaction.As Tregs are produced,CD147,which is expressed on their surface,is stimulated by CD98,which is widely expressed in the physiological environment.As a result,CD147’s intracellular domain binds to CDK2 and retains it near the membrane,leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation.In addition,the optimal distribution of Foxp3+Tregs under both pathological and physiological conditions depends on CD98 expression.Thus,our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment.More importantly,Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability,which has guiding significance for the application of Tregs in immunotherapy.