Ten years of substantial work by Nathalie Labrecque's team at the Montreal Clinical Research Institute (IRCM) and the Maisonneuve-Rosemont Hospital Research Center have shed new light on the mechanisms governing an effective immune response to infections. The results are published in the prestigious Journal of Experimental Medicine.
While the role of the immune system and its lymphocytes in the fight against infectious agents has long been established in the scientific literature, many crucial aspects of the cellular and molecular mechanisms that trigger and regulate the T-cell response still elude scientific understanding.
Labrecque's team, in collaboration with, among others, Dr. Ivan Maillard of the University of Pennsylvania, a senior co-author of the study, focused on the early events in the response of immune cells called CD8+ T lymphocytes. In this long-term work, the team and its collaborators demonstrated that the NOTCH signalling pathway, conserved throughout the evolution of all multicellular organisms, plays an essential role in the differentiation (programming) process required for CD8+ T cells to become competent at controlling infection. The team also showed that among other things, NOTCH also enables the action of other transcription factors.
What is the context?
It is well known that when a naive CD8+ T lymphocyte (a sentinel cell circulating in the body) recognizes an infectious agent, it must rapidly create an army of fighting cells to combat the infection. Following infection, the majority of these fighting cells will die, but a proportion will be preserved to remember the identity of the attacking agent, and thus, be able to recognize it in the event of reinfection: these are the memory T cells. The creation of these fighting cells requires a new programming of CD8+ T cells, a process known as differentiation. Previous work by the team had shown that the NOTCH signalling pathway played a central role in differentiation, which is essential for an effective immune response by CD8+ T cells.
What is new?
In the present publication, the team has demonstrated that the NOTCH signalling is involved from the very first days of the CD8+ T cell differentiation period, which lasts around 7 to 10 days.
Observing the origin of the NOTCH signal - communicated via the NOTCH ligand to CD8+ T lymphocytes - the team was able to demonstrate that the recognition of an infectious agent by CD8+ T lymphocytes in the lymph nodes is what enables them to receive the NOTCH signal. To the team's surprise, it is structural cells called reticular fibroblasts, present in the lymph nodes, that have the essential task of providing the ligand for the NOTCH signal, in order to trigger the subsequent differentiation events of the CD8+ T lymphocyte.
"It is as if the dendritic cells signal the presence and the identity of the threat, but it's actually the fibroblastic cells that hold the code for programming the fighting cells," explains PhD student and first author of the study, Laure Le Corre.
Finally, the activation of NOTCH, following interaction with its ligands, leads to its cleavage and entry into the nucleus, where the DNA is located. There, it will bind to the DNA and open up part of it (chromatin) to enable the activation of other transcription factors that will induce the changes required (gene expression) for CD8+ T cell differentiation.
"There was some evidence that fibroblasts in the lymph nodes were involved in the CD8+ T cell response, but very little was known about the underlying mechanism, explains Nathalie Labrecque, professor in the Department of Medicine and Medical Specialties at UdeM. Our study adds an important piece to the puzzle and really advances the field."
What is next?
The present study focused specifically on the immune response involving the NOTCH signalling pathway in an early infection context. These new understandings could open up further observations of the collaboration between the NOTCH signalling pathway and other transcription factors involved in the early immune response.
A further step will be to shed light on how this process takes place in the context of chronic infection or cancer, in particular, to better understand the more advanced phases of the mechanisms governing the immune response. For instance, an interesting avenue would be to understand whether, in these cases, the signal also comes from the fibroblast niche.
These new insights could pave the way for innovative therapeutic targets to improve the immune response, to understand what happens in this respect when infection becomes chronic, and also when the aggression is not of external origin, such as in cancer.
About this study
The article "Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation" by Laure Le Corre and al. was published in the Journal of Experimental Medicine on March 20, 2025.
This study was made possible by the Canadian Institutes of Health Research and the National Institutes of Health (USA).
