The Role of Transforming Growth Factor-Beta in T-Cell Signalling

Abstract

Transforming Growth Factor beta (TGFβ) is a pivotal cytokine in regulating our immune responses. TGFβ exerts many effects through T-cells, which are an important cell type in fighting infection. Functionally, TGFβ can inhibit the differentiation of naïve T-cells to pro-inflammatory T helper 1 (Th1) or Th2 cells. Conversely, TGFβ can promote the development of both pro-inflammatory Th17 cells and anti-inflammatory regulatory T-cells (Tregs). Interestingly, TGFβ exists as three isoforms with varying functions that mediate a wide scope of effects on T-cells through the same signalling machinery via Smad transcription factors, typically through Smad2, Smad3 and Smad4, and TIF1γ. However, the current mechanisms for how the TGFβ isoforms and the Smad transcription factors account for such variability in T-cell function are unclear.Here, we developed a system for exploring Smad signalling dynamics within a T-cell context using Jurkat T-cells. Our data demonstrates that Smad2 and Smad3 have varying signalling dynamics to each other and between the isoforms of TGFβ. We further demonstrate that the isoforms cause a different genetic profile in T-cells to each other and mediate gene transcription in varying reliance on specific Smads. In brief, TGFβ1 appears to favour Smad2 nuclear translocation, TGFβ2 requires Smad2, Smad3 and Smad4, and TGFβ3 has a preference for Smad3 nuclear translocation. These data indicate a more intricate mechanism of TGFβ signalling in T-cells.

Date of Award	1 Aug 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Supervisor) & Pawel Paszek (Supervisor)