Differential synergy of Notch and T cell receptor signaling determines αβ versus γδ lineage fate

Abstract

Thymic precursors expressing the pre–T cell receptor (TCR), the γδTCR, or the αβTCR can all enter the CD4+8+ αβ lineage, albeit with different efficacy. Here it is shown that proliferation and differentiation of precursors with the different TCRs into αβ lineage cells require Notch signaling at the DN3 stage of thymic development. At the DN4 stage, Notch signaling still significantly contributes to the generation of αβ T cells. In particular, in αβ lineage commitment, the pre-TCR synergizes more efficiently with Notch signals than the other two TCRs, whereas γδTCR-expressing cells can survive and expand in the absence of Notch signals, even though Notch signaling enhances their proliferation. These observations suggest a new model of αβ versus γδ lineage choice in which lineage fate is determined by the extent of synergy between TCR and Notch signaling and in which the evolutionarily recent advent of the cell-autonomously signaling pre-TCR increased the efficacy of αβ T cell generation.

Specific Notch receptor–ligand interactions control human TCR-ab/gd development by inducing differential Notch signal strength

“…However, it has remained unclear which receptor-ligand interactions are involved in these processes and, moreover, the Notch dependency for TCR- and TCR- T cell development was shown to be different between both species (Washburn et al, 1997;De Smedt et al, 2002;García-Peydró et al, 2003;Ciofani et al, 2006;Garbe et al, 2006;Taghon et al, 2006;Van de Walle et al, 2009). Here, we demonstrate that differential Notch receptor-ligand interactions control human TCR- and TCR- T cell development by inducing different Notch signal strengths and show that the Jagged2-Notch3 interaction is critical for human  T cell development.…”

“…In both mouse and human, Notch signal strength modulates TCR- and TCR- T cell development (Washburn et al, 1997;De Smedt et al, 2002;García-Peydró et al, 2003;Ciofani et al, 2006;Garbe et al, 2006;Taghon et al, 2006;Van de Walle et al, 2009), a process which, in vivo, occurs in the cortex (Petrie and Zúñiga-Pflücker, 2007). We have recently shown that JAG2 is expressed by the majority of human cortical TECs, in addition to DLL4 which is less abundantly expressed in this region , indicating that both ligands can mediate the development of both T cell subsets.…”

“…Importantly, the early up-regulation of Notch3 during human T cell development in comparison with the mouse might explain the difference in Notch dependency of TCR- and TCR- T cell differentiation that is observed between both species (Washburn et al, 1997;Ciofani et al, 2006;Garbe et al, 2006;Taghon et al, 2006;Van de Walle et al, 2009). In humans, both types of T cells start to diverge at the CD34 + CD1 + stage when Notch3 is already highly expressed ( Van de Walle et al, 2009), allowing Notch3 to influence this lineage choice through activation of Jagged2 that is abundantly expressed by human TECs ( Van de Walle et al, 2011).…”

“…In both mouse and human, Notch signal strength can modulate the / T cell lineage choice (Washburn et al, 1997;Ciofani et al, 2006;Garbe et al, 2006;Taghon et al, 2006;Van de Walle et al, 2009), but the mechanisms through which this is achieved are still unknown. Because we have recently shown that the Notch ligands DLL4, JAG1, and JAG2 are expressed by human thymic epithelial cells (TECs) and that these ligands induce different levels of Notch1 signal strength ( Van de Walle et al, 2011), we investigated their impact on human TCR- and TCR- T cell development.…”

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.…”