TOX Is Required for Development of the CD4 T Cell Lineage Gene Program

Abstract

The factors that regulate thymic development of the CD4+ T cell gene program remain poorly defined. The transcriptional regulator ThPOK is a dominant factor in CD4+ T cell development, which functions primarily to repress the CD8 lineage fate. Previously, we showed that nuclear protein TOX is also required for murine CD4+ T cell development. Here we sought to investigate if the requirement for TOX was solely due to a role in ThPOK induction. In apparent support of this proposition, ThPOK upregulation and CD8 lineage repression were compromised in the absence of TOX, and enforced ThPOK expression could restore some CD4 development. However, these “rescued” CD4 cells were defective in many aspects of the CD4+ T cell gene program, including expression of Id2, Foxo1, and endogenous Thpok, among others. Thus, TOX is necessary to establish the CD4+ T cell lineage gene program, independent of its influence on ThPOK expression.

The many roles of TOX in the immune system

“…Similar phenotype cells were also reported in mice expressing a hypomorphic ThPOK allele [22]. However, expression of a ThPOK transgene (ThPOK-Tg ) in TKO mice did not result in a complete rescue of the TKO phenotype [21]. While the CD8 lineage was inhibited in these animals, indicating that the alternative fate repression function of ThPOK was not dependent on TOX, the CD4 lineage was still aberrant.…”

“…These cells expressed low levels of ThPOK [14,21], pointing to TOX as an upstream regulator of ThPOK. Similar phenotype cells were also reported in mice expressing a hypomorphic ThPOK allele [22].…”

Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma

“…[13][14][15]30,31 The roles of TOX in immune system development are relatively wellcharacterized since its discovery 13 ; however, its role in human cancer has not been reported. On the basis of our findings, TOX has emerged as a key player, when expressed ectopically, in driving malignant cell transformation in CTCL.…”

“…Mice deficient in TOX failed to develop CD4 1 T-cell lineage; however, on the newly formed CD4 1 T cells exiting the thymus, TOX is tightly downregulated and remains suppressed in the mature CD4 1 T cells in the skin and blood. [13][14][15] Therefore, the observation of TOX expression in MF skin biopsy specimens is highly unusual. Whether TOX contributes to CTCL pathogenesis has not been investigated.…”

TOX2 regulates human natural killer cell development by controlling T-BET expression

“…1 T lineages, and NK cells, 17,20,21 the function of TOX2, particularly in human lymphoid development, have not been studied. Here we show that TOX2 is preferentially expressed in human NK cells among various leukocyte populations and is required for in vitro and in vivo human NK cell differentiation from UCB-derived CD34…”