Stage-Specific and Differential Notch Dependency at the αβ and γδ T Lineage Bifurcation

Abstract

Signals transduced by Notch receptors are indispensable for T cell specification and differentiation of alphabeta T lineage cells. However, the role of Notch signals during alphabeta versus gammadelta T lineage decision remains controversial. Here, we addressed this question by employing a clonal analysis of CD4(-)CD8(-) (DN) progenitor potential to position the divergence of alphabeta and gammadelta T cell lineages to the late DN2 to DN3 developmental stages. Accordingly, alphabeta and gammadelta precursor frequencies within these T cell progenitor subsets were determined, both in the presence and absence of Notch signaling through Delta-like 1. Notch signals were found to be critical for the DN to CD4(+)CD8(+) (DP) transition, irrespective of the identity (pTalphabeta or gammadelta) of the inducing T cell receptor complex, whereas gammadelta T cells developed from gammadeltaTCR-expressing T cell progenitors in the absence of further Notch ligand interaction. Collectively, our findings demonstrate a differential, stage-specific requirement for Notch receptor-ligand interactions in the differentiation of alphabeta and gammadelta T cells from T cell progenitors.

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

“…The mechanism by which Notch enables γδ17 development appears complex and may involve several distinct functions of the Notch signaling pathway. One key role of Notch signaling in γδ17 development appears to be enhancing expansion and survival of γδ T-cell precursors, consistent with previous reports 14, 53 . Specifically, Notch signaling appears to provide protection from the deleterious effects of cytokine signaling by inhibiting Il6r expression and inducing IL-6R shedding.…”

“…Retroviral constructs were generated, as previously described 14, 53, 58 , by subcloning the cDNAs of interest into the pMigR1 or pMIY plasmids, upstream of the internal ribosomal entry site 59, 60 . Stable retroviral-producing GP+E.86 packaging cell lines were generated for each construct.…”

Current progress in γδ T-cell biology

“…SOX13, 1 Id3, 2 T-cell receptor (TCR) signal strength, etc. [3][4][5][6][7][8][9][10] However, mechanisms of functional differentiation of effector cd T cells are poorly understood. [11][12][13][14] Key cytokines produced by cd T cells are interferon (IFN)-c, [15][16][17][18][19] tumor-necrosis factor (TNF)-a 20,21 and IL-17, [22][23][24][25][26] and are critical for pathogen clearance, immune regulation and autoimmunity.…”

Temporal Predisposition to αβ and γδ T Cell Fates in the Thymus

“…Notably, TCRgd can also mediate bselection-like differentiation to the DP stage. This is most evident in animals unable to express a functional pre-TCR, in TCRgd Tg mice in vivo (8,10,(19)(20)(21)(22)(23), and in cultures in which TCRgdexpressing progenitor cells are allowed to develop in vitro (24)(25)(26). Like b-selected DP cells, gd-selected DP cells silence TCRg gene expression and undergo TCRa rearrangements, indicating that they are bona fide ab-lineage cells (21).…”

“…Using the OP9-DL1 coculture system (38), it was proposed that commitment initiates at the DN2 stage and is completed at the DN3 stage. This was based on the finding that single DN3 cells give rise to either TCRab + or TCRgd + cells, but rarely both (24). However, the absence of CD4 and CD8 expression analysis precludes definitive conclusions with regard to ab/gd-lineage commitment, particularly because TCRgd expression in progenitor cells is known to result in the production of both gd and DP cells (24).…”