TCR-mediated ThPOK induction promotes development of mature (CD24−) γδ thymocytes

Abstract

T lymphocytes develop into two major lineages characterized by expression of the ab and cd T cell receptor (TCR) heterodimers. Within each major lineage, further specialization occurs, resulting in distinct subsets that differ in TCR specificity, phenotype and functional attributes. Thus, in the murine thymus, two distinct subsets of mature (CD24À) cd cells have been identified, that is NK1.1 þ cells, which are enriched for Vc1.1 usage and selectively produce IFNc on stimulation, and CCR6 þ cells, which are enriched for Vc2 usage produce IL17. The upstream signals and transcriptional pathways that promote development of these distinct cd subsets remain relatively poorly understood. Here, we show that the Zn-finger transcription factor ThPOK has a critical function in the development of cd thymocytes. Thus, lack of functional ThPOK causes a marked reduction in the percentage and absolute number of mature cd thymocytes, and a particularly severe reduction of NK1.1 þ cells. Conversely, constitutive ThPOK expression leads to a striking increase in mature NK1.1 þ cd thymocytes. Further, we show that ThPOK induction in cd thymocytes is induced by strong TCR signals mediated by engagement with antibody or high-affinity endogenous ligands, and that an important ThPOK cis-acting element, the distal regulatory element (DRE), is sufficient for this TCR-dependent induction. These results show that ThPOK expression in cd thymocytes is regulated in part by the strength of TCR signalling, identify ThPOK as an important mediator of cd T cell development/maturation, and lend strong support to the view that development of a significant fraction of cd T cells depends on TCR engagement/ signalling.

Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

“…Because strong TCR signals have been thought to be involved in helper lineage choice (13) and ThPOK expression (14), differences in TCR affinity to self-peptide would affect the initial amount of ThPOK protein and thereby be involved in cell fate discrimination in Thpok DTE/DTE mice. It was therefore important to test whether redirected differentiation occurs when all thymocytes expressed the identical TCR.…”

The BTB-ZF transcription factors

“…76 Th-POK is required for the normal maturation of invariant NKT cells 17,77 as well as for the optimal development of γδ T cells. 78 PLZF is also essential for the development of a variety of innate T cells, including effector NKT cells [79][80][81] and innate γδ T cells. [82][83][84] The effect of PLZF on innate γδ T cell development is not an intrinsic one, however, and instead requires the secretion of IL-4 by PLZF + NKT cells.…”

Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas

“…In the context of conventional T-cell development, we previously provided the first evidence to our knowledge that ThPOK acts as a master regulator of the CD4/CD8 decision point, whose presence or absence dictates development to the CD4 or CD8 lineages, respectively (2, 4). Later we found that ThPOK also plays a widespread and critical role in development of nonconventional T-cell subsets like iNKT cells and selected γδ T-cell subsets (6,39,40). In all of these mature T-cell lineages, ThPOK is expressed at more-or-less high levels under normal physiological conditions.…”

“…Alternate commitment to either the CD4 or CD8 lineages is controlled by the Zn finger transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK), whose expression is necessary and sufficient to direct development to the CD4 lineage (1)(2)(3)(4). Strong antibody-mediated stimulation can induce ThPOK in developing thymocytes, indicating that ThPOK expression is controlled by TCR signaling (5,6). A loss-of-function mutation of ThPOK does not affect the efficiency of positive or negative selection (4).…”