TRAT1 protein revealed as molecular switch in T helper cells

Researchers at the Medical University of Vienna have uncovered how a little-studied protein, TRAT1 (T Cell Receptor Associated Transmembrane Adaptor 1), acts as a molecular switch in the immune system. By controlling the activity of T helper cells, TRAT1 balances immune attack and restraint - a mechanism critical for preventing excessive inflammation and autoimmune disease. The findings were published in Cell Communication and Signaling [1].

T helper cells are the ‘conductors’ of the immune system, directing other immune cells and tailoring responses to specific threats. They are divided into effector T cells, which actively attack invaders, and regulatory T cells (Treg), which restrain immune activity. Until now, the precise molecular signals controlling this balance were poorly understood.

The Vienna team, led by Ralf Schmidt and Klaus Schmetterer, applied a combination of advanced cellular and molecular techniques to study TRAT1 function. Primary human CD4⁺ T cells - including thymus-derived and induced Treg cells - were genetically modified using CRISPR/Cas9-mediated deletion or retro-/lentiviral overexpression of TRAT1. Functional assays, flow cytometry, cytokine quantification, and RNA sequencing revealed how TRAT1 modulates T cell activity. Mechanistic studies included pathway inhibition with small molecules and phospho-protein analysis, while the effect of TRAT1 on Treg function was further assessed in a CAR-Treg context using an immune organoid model of allo-rejection.

The results show that TRAT1 acts differently depending on the T cell subtype. In effector T cells, TRAT1 ensures controlled activation: deleting it boosts activity but reduces production of inflammatory messengers such as interleukin-17. In Treg cells, TRAT1 supports targeted suppressive functions, enhancing inhibition of some immune cell types more than others.

“TRAT1 acts like a molecular switch, controlling both immune attack and suppression,” explained study leader Klaus Schmetterer. “Understanding this dual role could help us design targeted therapies for autoimmune diseases and transplant rejection.”

Importantly, altered TRAT1 expression was observed in patients with graft-versus-host disease (GvHD) and systemic lupus erythematosus, indicating disrupted T helper cell signalling in these conditions. These insights could guide the development of cell-based immunotherapies, such as tailor-made CAR-Treg cells to prevent unwanted immune reactions. Proof-of-concept work has already been demonstrated in a novel 3D cell culture model for transplant rejection, according to first author Tobias Frey.

More information online

1. T cell receptor associated transmembrane adaptor 1 (TRAT1) modulates human Th17 published in Cell Communication and Signaling