As part of Marc Dalod’s team, Karine Crozat, Yannick Alexandre and their coworkers have shed new light on the role played by dendritic cells in activating and maintaining immunological memory response. Already known for their capacity to activate cytotoxic T lymphocytes during the “immune priming” step (the first contact between still-naïve T cells and the antigen, leading to their differentiation into killer cells), a sub-population of dendritic cells, called XCR1, also contributes to reactivating these lymphocytes when they encounter the same pathogen or tumor agent again.
For many years, we have known that dendritic cells (DC XCR1) play a key role in initiating immune response during the first infection by a pathogen. Conversely, most scientists consider that dendritic cells’ involvement in the so-called secondary response to be negligible. It is generally accepted that memory cytotoxic T lymphocytes (mCTLs), already sensitive to the enemy, indeed need fewer signals to be activated. They therefore do not need expert cells in the presentation of antigens such as XCR1 DCs. Today, Marc Dalod’s team is challenging this principle.
To carry out their work, the team has developed an original murine model in which the various players in immune response can be monitored in real time using fluorescence and XCR1 DCs can be eliminated “on request”: present during the first meeting with the pathogen or tumor agent, these cells are selectively eliminated just before the mCTLs come into play.
In this case, the observations made by Marc Dalod’s team leave no doubt: mCTLs are reactivated less effectively when XCR1 DCs are absent. This discovery widens the range of our understanding of the role of dendritic cells. Thus, XCR1 DCs do not just present antigens to mCTLs, they produce cytokines and chemokines (“hormones” in the immune system such as IL12, CXCL9, etc.) which orchestrate mCTL reactivation in time and in space.
During the second attack, the XCR1 DCs have a dialogue in the spleen with their immune partners (the main being Natural Killer and helper T cells) in order to “wake up” mCTLs, as well as to maintain their activity.
A choreography unique to each pathogen
This dialogue, required to activate the secondary immune response, varies with the pathogen. “Depending on its profile, it preferentially activates a given type of immune cells, in turn leading to the production of distinct cytokines or chemokines. Some pathogens will cross paths with the XCR1 DCs which, in response, will then produce molecules such as IL-12 and CXCL9, conditioning the reactivation of memory T cells,” Marc Dalod explained.
In this context, XCR1 DCs may be precious allies in treating infectious diseases and cancers. The team has already demonstrated that, in Listeria infections, mice without XCR1 DCs have less effective CTL responses and a heavy bacterial load. Several studies have also shown that XCR1 DCs promote CTLs’ protective functions in murine melanoma models. “In mice without XCR1 DCs, anti-PD1 antibodies also turned out to be ineffective in the case of melanoma and thymoma,” Marc Dalod pointed out. “So it is not enough to block PD-1 to unlock the immune response, mCTLs also have to receive signals from the XCR1 DCs to be reactivated.”
In humans, correlations have been observed between the genes’ level of intra-tumor expression specifically expressed by XCR1 DCs and the patients’ ability to control their tumors. These preliminary results lead us to believe that XCR1 DCs are indeed functionally involved in effector and memory mechanisms leading to anti-tumor cytotoxic T lymphocyte defense in humans.
“Today, our project extends from research on specific diagnostic and therapeutic targets for XCR1 DCs (using compared analyses of gene expression programming between humans and mice) to pursuing functional exploration of these cells with various animal models,” Marc Dalod concluded.
Source:
XCR1+ dendritic cells promote memory CD8+ T cell recall upon secondary infections with Listeria monocytogenes or certain viruses.
Yannick O. Alexandre, Sonia Ghilas, Cindy Sanchez, Agn.s Le Bon, Karine Crozat, and Marc Dalod
More information about the lab
