The interplay between the CD4-1ineage transcription factor ThPok and the CD8-iineage transcription factor, runt-related transcription factor 3 （Runx3）, in T-cell development has been extensively documented. However,...The interplay between the CD4-1ineage transcription factor ThPok and the CD8-iineage transcription factor, runt-related transcription factor 3 （Runx3）, in T-cell development has been extensively documented. However, little is known about the roles of these transcription factors in invariant natural killer T （iNKT） cell development. CDld-restricted iNKT cells are committed to the CD4＋CD8- and CD4-CD8- sublineages, which respond to antigen stimulation with rapid and potent release of T helper （Th） 1 and Th2 cytokines. However, previous reports have demonstrated a new population of CD8~ NKT cells in ThPok-deficient mice. In the current study, we sought to determine whether Runx3 was involved in the re-expression of CD8 and function of iNKT cells in the absence of ThPok. We used mice lacking Runx3, ThPok or both and verified that Runx3 was partially responsible for the appearance of CD8^＋ iNKT cells in ThPok knockout mice. Additionally, Runx3 participated in the immune response mediated by iNKT cells in a model of α-galactosylceramide-induced acute hepatitis. These results indicate that Runx3 is crucial for the phenotypic and functional changes observed in ThPok-deficient iNKT cells.展开更多
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 ...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.展开更多
文摘The interplay between the CD4-1ineage transcription factor ThPok and the CD8-iineage transcription factor, runt-related transcription factor 3 （Runx3）, in T-cell development has been extensively documented. However, little is known about the roles of these transcription factors in invariant natural killer T （iNKT） cell development. CDld-restricted iNKT cells are committed to the CD4＋CD8- and CD4-CD8- sublineages, which respond to antigen stimulation with rapid and potent release of T helper （Th） 1 and Th2 cytokines. However, previous reports have demonstrated a new population of CD8~ NKT cells in ThPok-deficient mice. In the current study, we sought to determine whether Runx3 was involved in the re-expression of CD8 and function of iNKT cells in the absence of ThPok. We used mice lacking Runx3, ThPok or both and verified that Runx3 was partially responsible for the appearance of CD8^＋ iNKT cells in ThPok knockout mice. Additionally, Runx3 participated in the immune response mediated by iNKT cells in a model of α-galactosylceramide-induced acute hepatitis. These results indicate that Runx3 is crucial for the phenotypic and functional changes observed in ThPok-deficient iNKT cells.
基金supported by Duke University Center for AIDS Research(CFAR)Small Grant(Q.-J.L)National Institutes of Health(NIH)Training Grants(2 T32 Al 052077-11 and 5 T32 Al 052077-09)(E.R.)American Association of Immunologists(AAI)Careers in Immunology Fellowship(Q.-J.L and E.R.).
文摘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.
