Tipping points in T-cell differentiation
LMU researchers have dissected the mechanism by which the roquin protein regulates the activity of immune cells. The study also sheds new light on how roquin prevents autoimmune reactions.
A protein named roquin is known to play a crucial role in the control of the immune system. More specifically, roquin regulates the activity of so-called “helper” T cells. In its absence, T cells undergo spontaneous activation, which leads to autoimmune or autoinflammatory disease. In a paper that has just appeared in the journal “Nature Immunology”, a team led by Vigo Heissmeyer, Professor of Immunology at LMU and leader of a research group at the Helmholtz Center Munich (HMGU), reports that the spectrum of T-cell types that respond to roquin is larger than previously assumed. “In cooperation with colleagues at the HMGU, the TU München and the Walter and Eliza Hall Institute in Melbourne (Australia), we have shown for the first time that roquin regulates the differentiation of a subset of T helper cells called TH17, and we have uncovered the mechanism that underlies its effect on this process,” Heissmeyer explains. The new findings represent an important advance in our understanding of the origins of autoimmune disease.
TH17 cells play an essential role in combatting bacterial and fungal pathogens. However, they can sometimes be aberrantly activated by antigenic structures present on host tissues, or remain active after the elimination of an invasive organism. In such cases, the resulting immune reactions can lead to severe tissue damage. For instance, a genetically modified mouse strain that exhibits enhanced TH17 cell activity develops spontaneous inflammation of the lung and displays pathological changes in lung tissue reminiscent of those seen in cases of non-allergic asthma. “The observation that the same condition develops when the roquin-encoding genes are inactivated in T cells pointed to a direct functional connection between their products and TH17 activity,” Heissmeyer adds.
Roquin indeed acts to repress the formation of TH17 cells. It does so by binding to messenger RNAs which program the synthesis of proteins required for TH17 differentiation. Binding of roquin actually leads to the destruction of the mRNAs but, as Heissmeyer and colleagues have now shown, this requires the cooperation with a second factor. “Roquin interacts with the enzyme regnase-1, which controls an overlapping set of target genes with roquin. Both proteins are involved in the repression of TH17 differentiation, and they play mutually dependent roles in the process,” Heissmeyer explains.
But this is not all. As the new study now shows, a third factor, the enzyme MALT1, also contributes to the regulation of TH17 activity: MALT1 is essential for the inactivation of roquin. “MALT1 cleaves the roquin protein, thus destroying its biological activity. This provides for fine-tuning of the level of active roquin, and permits continuously variable control of T-cell differentiation. Moreover, the rate of roquin cleavage depends on the level of activation of the T-cell receptor by its cognate antigen on the target cell,” says Heissmeyer. If the receptor is strongly activated by a particular antigen, the concentration of roquin is correspondingly reduced. Conversely, lower levels of receptor activation induce less degradation of roquin. In other words, T-cell activity is controlled by the specific antigen bound to the T-cell receptor, and this in turn influences subsequent differentiation decisions: “Depending on the precise situation, a TH17 cell or another specialized T-cell type with a quite different function is formed,” Heissmeyer explains.
“These findings provide new insights into the basic molecular mechanisms involved in molecular regulation of the TH17 response which, when dysfunctional, has a tremendous pathological potential,” Heissmeyer points out. Hence the results are significant for the development of novel therapies for autoimmune disease, as they suggest that TH17 cell differentiation could perhaps be regulated by modulating roquin activity pharmacologically, or by regulating its function with the aid of MALT1 inhibitors.
(nature Immunology 2014) göd