Expression of the transcription factor cKrox in peripheral CD8 T cells reveals substantial postthymic plasticity in CD4-CD8 lineage differentiation

Abstract

Most T cells belong to either of two lineages defined by the mutually exclusive expression of CD4 and CD8 coreceptors: CD4 T cells are major histocompatibility complex (MHC) II restricted and have helper function, whereas CD8 T cells are MHC I restricted and have cytotoxic function. The divergence between these two lineages occurs during intrathymic selection and is thought to be irreversible in mature T cells. It is, however, unclear whether the CD4-CD8 differentiation of postthymic T cells retains some level of plasticity or is stably maintained by mechanisms distinct from those that set lineage choice in the thymus. To address this issue, we examined if coreceptor or effector gene expression in mature CD8 T cells remains sensitive to the zinc finger transcription factor cKrox, which promotes CD4 and inhibits CD8 differentiation when expressed in thymocytes. We show that cKrox transduction into CD8 T cells inhibits their expression of CD8 and cytotoxic effector genes and impairs their cytotoxic activity, and that it promotes expression of helper-specific genes, although not of CD4 itself. These observations reveal a persistent degree of plasticity in CD4-CD8 differentiation in mature T cells.

The Transcription Factor Zbtb7b Promotes CD4 Expression by Antagonizing Runx-Mediated Activation of the CD4 Silencer

“…The cessation of CD8 and the maintenance of CD4 coreceptor expression are two key events characteristic of CD4 cell differentiation. That Zbtb7b belongs to a family of proteins that generally act as transcriptional repressors (34,35) is in line with it repressing CD8 expression by targeting CD8 cis-regulatory elements, as we recently showed of the CD8 E8(I) enhancer (28,36,37). In contrast to its effect on CD8, the ability of Zbtb7b to promote CD4 expression obviously does not fit with a direct transcriptional repression effect.…”

Interferon-γ and interleukin-4 reciprocally regulate CD8 expression in CD8+T cells

“…Several transcription factors have been implicated in the control of CD8␣ gene expression, including STAT5 and STAT6 for which a putative binding site has been identified within the CD8 enhancer element E8 I (7), MAZR which binds enhancer E8 II and negatively regulates CD8 expression (31), cKrox which binds E8 I and negatively regulates both CD8 and IFN-␥ expression while up-regulating GATA-3 (32), and GATA-3 for which binding sites have been identified in both mouse and human CD8 enhancer regions (33,34). Two observations suggest that GATA-3 may have a role as a negative regulator: first, in the thymus, GATA-3 promotes CD4 lineage development while inhibiting CD8 lineage development (35); second, GATA-3 expression is induced in CD8 ϩ T cells exposed to IL-4 (36) or transduced with cKrox which, as noted above, down-regulates CD8 expression (32).…”

Epigenetic Silencing of Cd8 Genes by ThPOK-Mediated Deacetylation during CD4 T Cell Differentiation

“…Interestingly, thymocytes that are deficient in both ThPOK and RUNX3 are committed by default to the CD4 lineage (14), suggesting that ThPOK antagonizes RUNX3-mediated CD8 lineage choices in the process of CD4/CD8 lineage commitment. Indeed, the overexpression of ThPOK represses cytotoxic gene expression in CD4 (15) or mature CD8 T cells (16). However, it is still unknown whether ThPOK is responsible for CD8 silencing in the commitment of the CD4 lineage.…”