A Specific Signalling Signature Characterizes the Development of Naturally Occurring and Antigen-Specific Regulatory T Cells

Abstract

The molecular signals involved in the generation of thymic regulatory T cells (Treg) still remain controversial. It has been proposed that high avidity interactions are required for Treg selection. Here, we used double transgenic mice (TCR-HA × IgHA) and followed the kinetics and phosphorylation status of HA-specific Tregs that develop in the absence or presence of their agonist ligand expressed in the thymus, as well as of polyclonal “naturally ocurring” Tregs (nTregs). We found that, in basal conditions, nTregs showed enhanced basal phosphorylation of c-Cbl, Erk and PI3K, indicating their selection by high avidity ligands. However, in response to TCR cross-linking, both nTregs from Balb/c mice and HA-specific Tregs showed reduced levels of phosphorylated Erk1/2, c-Cbl and Akt. We conclude that thymus-derived Tregs display a characteristic “signalling signature” that suggests qualitative differences in TCR-mediated signalling that may not be explained merely by a higher TCR avidity.

Keywords:

• Regulatory T cell
• Signaling
• Development
• TCR transgenic
• FoxP3

ACKNOWLEDGMENTS

We thank QFB, Carlos Castellanos and Dr. Eduardo Infante (BD Biosciences) for technical assistance. We also thank MVZ Georgina Díaz and Jorge García for animal care assistance. This work was supported by Grants 42797-Q (GS) and 44212-Q (AS) from Conacyt, México, and from INSERM, France (AS). KN was supported by a fellowship from Conacyt (170032) and from DGEP, UNAM. DO was supported by a fellowship from DGEP, UNAM.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.