The innate immune response provides an important natural defense system that protects the organism against various types of infectious threats. Innate lymphoid cells (ILCs) are an important cellular actor in these early immune responses. Scientists in the Innate Immunity/Inserm U1223 Unit at the Institut Pasteur have discovered the existence of human ILC precursors (ILCP) that circulate in the blood and are therefore easily obtained. Using purified ILCP, it now becomes possible to generate different types of mature ILCs that could be used in cellular therapies.
Immune defense comprises two phases: an ‘innate’ immune response, that involves a family of innate lymphoid cells (ILCs), and an ‘adaptive’ immune response that follows several weeks after infection and comprises antibody-producing B cells and cytotoxic T cells that eliminate infection. “A strong innate immune response is essential for protection against disease”, states James Di Santo, head of the Innate Immunity Unit/Inserm U1223. “ILCs are important in the fight against diverse pathologies”. They contribute in the maintenance of homeostasis and support barrier function at mucosal sites. More generally, ILCs can protect against infection, cancer and metabolic diseases (obesity, diabetes) and allergies.
Until now, our knowledge of how ILC precursors (ILCP) give rise to different mature ILC subsets in tissues remained limited. The Innate Immunity Unit/Inserm U1223 at the Institut Pasteur discovered that ILCP are present in the blood: “We were able to identify, and importantly, isolate human ILCP”, emphasized James Di Santo. “Obtaining ILCP from the blood is quite simple compared to isolating mature ILCs that reside in tissues”. This discovery is the fruit of a long collaborative effort between the Institut Pasteur, Inserm, Universities Paris-Diderot and Paris-Sud as well as Paris Hospitals (AP-HP) and several international research centers.
The identification of circulating human ILCP and the ease in isolating them provides a means for future applications, including cell therapies. These precursors have the potential to develop into the four main subsets of innate lymphoid cells that provide early innate immune defense: natural killer (NK) cells as well as three types of ILCs (ILC1, 2 or 3) that have different roles and functions. “Using circulating ILCP, our laboratory has been able to produce the different types of mature ILCs, which can allow us to generate large quantities of specific ILCs for use in preventing or treating human diseases”, such as infections, different types of cancer, metabolic diseases or allergies.
This discovery also challenges the existing dogma concerning the origin of tissue ILCs. “The ‘factory’ for ILCs is probably not in the bone marrow," explains James Di Santo. "ILCP circulate in the blood and upon arrival at the site of infection or cancer for example, differentiate into mature ILCs that are required to combat the aggression. The production of ILCs is therefore local and dependent on the tissue involved. For this reason, we propose to call this process ‘ILC-poiesis’ similarly to other developmental systems within the organism”.
Systemic human ILC precursors provide a substrate for tissue ILC differentiation, Cell, March 9, 2017.
Ai Ing Lim,1,2,3 Yan Li,1,2 Silvia Lopez-Lastra,1,2,4 Ralph Stadhouders,5 Franziska Paul,6 Armanda Casrouge,1,2 Nicolas Serafini,1,2 Anne Puel,7,8 Jacinta Bustamante,7,8 Laura Surace,1,2 Guillemette Masse-Ranson,1,2 Eyal David,6 Helene Strick-Marchand,1,2 Lionel Le Bourhis,9 Roberto Cocchi,10 Davide Topazio,10 Paolo Graziano,10 Lucia Anna Muscarella,10 Lars Rogge,11 Xavier Norel,12 Jean-Michel Sallenave,3,13 Matthieu Allez,9,14 Thomas Graf,5 Rudi W. Hendriks,15 Jean-Laurent Casanova,7,8,16,17,18 Ido Amit,6 Hans Yssel,19 and James P. Di Santo1,2,20,*
1Innate Immunity Unit/Inserm U1223, Institut Pasteur, 75724 Paris, France
2Inserm U1223, 75015 Paris, France
3Universite´ Paris-Diderot, Sorbonne Paris Cite´ , 75205 Paris, France
4Universite´ Paris-Sud, Paris-Saclay, 91405 Orsay, France
5Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
6Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel
7Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, 75015 Paris, France
8Imagine Institute, 75015 Paris, France
9Inserm U1160, Institut Universitaire d’Hematologie, Hopital Saint-Louis, 75010 Paris, France
10Scientific Institute for Research and Health Care ‘‘Casa Sollievo della Sofferenza,’’ 71013 San Giovanni Rotondo, Italy
11Immunoregulation Unit, Institut Pasteur, 75724 Paris, France
12Inserm U1148, Laboratory for Vascular Translational Science (LVTS), CHU X. Bichat, 75877 Paris, France
13Inserm U1152, Faculte´ de Medicine site Bichat, Universite´ Paris Diderot, Universite´ Sorbonne Paris-Cite´ , 75018 Paris, France
14Gastroenterology Department, Hopital Saint-Louis, AP-HP, 75010 Paris, France
15Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, Netherlands
16St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
17Howard Hughes Medical Institute, New York, NY 10065, USA
18Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France
19Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, 75013 Paris, France