The Notch signaling pathway is a master regulator of CD8+ T cell exhaustion and differentiation during chronic infection
During chronic infection, the persistence of antigen and inflammation leads to the differentiation of CD8+ T cells into an exhausted state characterised by expression of inhibitory receptors (IRs) and the progressive loss of T cell functions. Among the different subsets of exhausted CD8+ T (Tex) cells, Tex progenitors expressing SLAMF6 and the transcription factor TCF-1 (TCF-1+) give rise to Tex…
During ongoing viral infections, the body's immune response can cause CD8+ T cells, which are crucial for fighting off pathogens, to enter a state of exhaustion. This exhaustion is marked by the expression of inhibitory receptors and a decline in the cells' ability to function effectively. Within this exhausted subset of CD8+ T cells, there are further divisions into different types, each with distinct features and functions.
One of the ways to potentially counteract this exhaustion is by blocking the PD-1/PD-L1 pathway, which can help restore the cells' functionality. However, the specific factors that control the transformation of CD8+ T cells into these exhausted states are not yet fully understood. Notch signaling, a molecular pathway that is activated during chronic infections due to persistent stimulation of T cells and inflammation, may play a role in this process.
To investigate the impact of Notch signaling on the exhaustion of CD8+ T cells, researchers studied mice that lack Notch1/2 expression only in mature CD8+ T cells. They found that the absence of Notch signaling led to severe exhaustion of these cells during chronic infection. The Tex cells, which are the exhausted T cells, expressed higher levels of inhibitory receptors and showed reduced functionality compared to their normal counterparts.
Furthermore, the study revealed that Notch signaling is crucial for the differentiation of Tex progenitors into the effector-like cells that have a more functional state. Additionally, stromal cells, which are part of the surrounding tissue, release specific ligands that provide Notch signals and are necessary for the differentiation of Tex cells throughout the course of the infection.
These findings suggest that Notch signaling plays a critical role in the transcriptional programming of exhausted CD8+ T cells, influencing their migration and ability to receive help from other immune cells, particularly CD4+ T cells. By impairing this transcriptional program, loss of Notch signaling drives Tex progenitor cells towards a more terminally exhausted fate, highlighting the importance of this signaling pathway in the regulation of T cell exhaustion during chronic infections.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
