Dynamic regulation of T cell activation by coupled feedforward loops

TL;DR

This paper investigates how coupled feedforward and feedback loops in T cell signaling regulate activation, ensuring responses are appropriately triggered and terminated, thus maintaining immune system balance.

Contribution

It introduces a novel coherent feedforward motif induced by the two-signal requirement and analyzes a composite feedforward-feedback motif involving helper and regulatory T cells.

Findings

The two-signal requirement induces a coherent feedforward motif suitable for immune response regulation.

Analysis of helper and regulatory T cell interactions reveals conditions for optimal T helper cell concentrations.

The proposed motifs align with the properties of an ideal immune response, balancing activation and deactivation.

Abstract

The adaptive immune system responds to foreign invaders by activating T cells. However, this response is perilous if T cells are activated by the wrong signal or if they remain activated unduly long after the threat has been eliminated. It is therefore important that T cells get activated only by the right kind of signals and for the right duration. The dominant theory in immunology over recent decades has been that a T cell must receive at least two signals before it can become activated. It is, however, unclear whether and how this two-signal requirement ensures that T cell activation is provoked only by the right signals and that the response is just long enough. Here, we propose that the two signal requirement induces a novel coherent feedforward motif whose properties align with those preferred for an ideal immune response. Further consideration of the interaction between helper and regulatory T cells induces a composite feedforward-feedback motif, analysis of which generates a condition for a healthy concentration of activated T helper cells.