Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

Abstract

SUMMARY Gradations in ERK signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as Rsk, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of γδ T cells. Instead, development of γδ T cells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the γδ fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes.

HEB is required for the specification of fetal IL-17-producing γδ T cells

“…TCR signalling involves activation of the PKCθ pathway, leading to activation of NFκB; the PI3K pathway, leading to activation of NFAT; and the MAPK signalling pathway (in particular, ERK), which is upstream of many inducible transcription factors, including Egr3 34 . MAPK signalling and Egr3 activity have been linked to the αβ/γδ T cell 19 and γδT17/γδT1 cell lineage choices 17 , 35 , 36 , in agreement with the signal strength model. However, other experiments have indicated that strong TCR signals are needed for the development of at least some γδT17 cells 16 .…”

Developmental origins of murine γδ T‐cell subsets

“…By contrast, a body of evidence instead suggests that γδ 17 cell development requires weak (or even absent) TCR γδ signalling . For example, generation of γδ 17 cells is favoured by the reduction of ERK activity . In addition, V γ 5V δ 1 + γδ T cells developing in the absence of Skint1 adopt IL‐17‐secreting characteristics .…”

“…Activation of the extracellular signal‐regulated kinase (ERK) pathway appears to be important, which can induce early growth response (Egr) family transcription factors and inhibitor of DNA binding 3 (Id3) . More recently, non‐canonical targeting of docking site for ERK, FXF (DEF) domain containing ERK substrates through the ERK DEF‐binding pocket has also been implicated in γδ T‐cell fate commitment . Hence, strong TCR signalling delivered mainly by TCR‐ γδ complexes drives DN cell commitment to the γδ T‐cell lineage.…”

Regulation of γδ T Cell Effector Diversification in the Thymus

“…More recent work has begun to shed light on the mechanism by which DN cells translate differences in signal strength and ERK signaling into alternative lineage fates. γδ T cell development is dependent on a non-canonical mode of ERK action mediated by its DEFbinding pocket (29). This domain is favored by strong and more prolonged signals and enables ERK to bind a distinct set of proteins required for γδ lineage adoption.…”

“…γδ T cell effector fate choice is also influenced by specific TCR signal transduction pathways. For example, ERK signals support the type 1 program as ERK-deficient TCRβ −/− mice have an increased frequency of CD27 − γδ T cells, and ERK-deficient KN6 γδ TCR transgenic thymocytes are skewed toward IL-17A production compared to the controls that predominately produce IFNγ (29). More recently, it was revealed that the tyrosine kinase Syk is selectively required for Tγδ17 development, through activation of the PI3K/Akt pathway downstream of γδTCR signaling (58).…”