The role of innate lymphoid cells (ILCs) during tuberculosis infection is poorly understood. A study published in the journal Cell Reports shows that infection of mice leads to local differentiation of ILCs called "ILC1-like" from immature precursors. ILC1-like have a distinct phenotype and metabolism, have protective potential, and their generation, stimulated by BCG vaccination, highlights their possible importance in protecting against TB.
Tuberculosis remains one of the most deadly infectious diseases, with approximately 10 million new cases and more than 1.5 million deaths each year. Research on immune defenses against the tuberculosis bacillus, M. tuberculosis, is largely dominated by the study of the contribution of macrophages, the main cells infected by the bacillus in the lungs, and T cells. New players in anti-tuberculosis immunity, including unconventional immune cells residing in tissues, are currently the focus of important research. Among these cells, innate lymphoid cells (or ILCs) represent a cell population discovered only 15 years ago. These cells reside in tissues where they play a dual role in maintaining tissue integrity and protecting against infection by pathogens. Innate lymphoid cells exist in different populations called ILC1, ILC2 and ILC3 depending on their biological properties. In mouse lung tissue, ILC2, the majority population of ILCs, play a critical role in diseases such as asthma and parasitic infections. Conversely, ILC1 and ILC3 contribute to immunity against intracellular (viruses, bacteria) and extracellular (bacteria, fungi) pathogens respectively. How these cells, present in the tissue at the time of infection, are influenced by M. tuberculosis infection and contribute to anti-tuberculosis immunity is beginning to be explored.
In an international collaboration, scientists found that during M. tuberculosis infection of mice, innate lymphoid cells behave differently: while ILC1 and ILC3 expand and become activated, ILC2 contract and become functionally inhibited. The researchers found that an atypical population that shares common characteristics with ILC1 but is distinct, called "ILC1-like" cells, appears in the lungs of infected mice.
Because immature ILC precursors in the lungs also increase in size during infection and begin to express ILC1 markers, the scientists hypothesized that the ILC1-like cells could originate from these immature ILCs. Using a series of approaches, they found that the inflammatory and metabolic environment impacts immature lung ILC precursors to differentiate into ILC1-like cells. Cytokines, which are key mediators of immune cell communication, produced during M. tuberculosis infection determine this differentiation process into ILC1-like cells. They also found that ILC1-like cells have a distinct metabolism and that glucose utilization is essential for their differentiation as well as their function. Finally, they found that ILC1-like cells have the potential to protect against M. tuberculosis infection and, interestingly, that intranasal administration of the anti-tuberculosis vaccine, BCG, results in the generation of these cells.
Taken together, these results support a model in which a precursor population contributes to the local differentiation of ILC1-like protective cells under the influence of an inflammatory and metabolic environment induced by M. tuberculosis infection. This study provides the basis to further explore the potential of ILC1-like cells in infectious as well as non-infectious domains. Approaches to specifically induce or inhibit the differentiation of ILC1-like cells could help to understand their contribution in various physio-pathological contexts and offer new immunological intervention strategies.
ILC precursor cells characterized by the expression of the interleukin-18 receptor (IL18R-alpha) and the transcription factor TCF-1 reside in lung tissue. Under homeostatic conditions, these cells show a bias towards an ILC2 phenotype (expression of the transcription factor GATA3, the metabolic factor Arg1 and the expression of interleukin-5 (IL-5). During M. tuberculosis infection, the inflammation induced in the lungs leads to the production of cytokines such as IL-12, IL-18 and IFN-gamma. This inflammatory environment shapes the fate of the precursor cells by promoting the acquisition of an ILC1 type phenotype such as the expression of the transcription factor T-bet, integrin CD49a or IFN-gamma, while disfavoring an ILC2 phenotype. Furthermore, this differentiation process requires the induction of a glycolytic program dependent on the presence of glucose in the metabolic environment. The newly differentiated ILC1-like cells exhibit protective capabilities and may participate in the elimination of M. tuberculosis from the lungs. (Created with BioRender.com) © Denis Hudrisier
“ILC precursors differentiate into metabolically distinct ILC1-like cells during Mycobacterium tuberculosis infection”
Dan Corral, Alison Charton, Maria Z Krauss, Eve Blanquart, Florence Levillain, Emma Lefrançais, Tamara Sneperger, Zoï Valhas, Jean-Philippe Girard, Gérard Eberl, Yannick Poquet, Jean-Charles Guéry, Rafael J Arguello, Yasmine Belkaid, Katrin D Mayer-Barber, Matthew R Hepworth, Olivier Neyrolles*, Denis Hudrisier*
Cell Reports April 19, 2022 - DOI: 10.1016/j.celrep.2022.110715
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