TY - JOUR
T1 - CD45RA+CD62L- ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs
AU - Kokkinou, Efthymia
AU - Pandey, Ram Vinay
AU - Mazzurana, Luca
AU - Gutierrez-Perez, Irene
AU - Tibbitt, Christopher Andrew
AU - Weigel, Whitney
AU - Soini, Tea
AU - Carrasco, Anna
AU - Rao, Anna
AU - Nagasawa, Maho
AU - Bal, Suzanne M.
AU - Jangard, Mattias
AU - Friberg, Danielle
AU - Lindforss, Ulrik
AU - Nordenvall, Caroline
AU - Ljunggren, Malin
AU - Haapaniemi, Staffan
AU - Keita, Åsa V.
AU - Söderholm, Johan
AU - Hedin, Charlotte
AU - Spits, Hergen
AU - Bryceson, Yenan T.
AU - Mjösberg, Jenny
N1 - Publisher Copyright: © 2022 The Authors.
PY - 2022/4/15
Y1 - 2022/4/15
N2 - Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA+ ILCs. CD45RA+CD62L+ ILCs (CD62L+ ILCs) resembled circulating naïve ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA+CD62L- ILCs (CD62L- ILCs) were epigenetically similar to CD62L+ ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L+ and CD62L- ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L+ and CD62L- ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L- ILCs with preferential differentiation capacity toward IL-22-producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L+ and CD62L- ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.
AB - Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA+ ILCs. CD45RA+CD62L+ ILCs (CD62L+ ILCs) resembled circulating naïve ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA+CD62L- ILCs (CD62L- ILCs) were epigenetically similar to CD62L+ ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L+ and CD62L- ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L+ and CD62L- ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L- ILCs with preferential differentiation capacity toward IL-22-producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L+ and CD62L- ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.
UR - http://www.scopus.com/inward/record.url?scp=85128487756&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciimmunol.abj8301
DO - https://doi.org/10.1126/sciimmunol.abj8301
M3 - Article
C2 - 35427178
SN - 2470-9468
VL - 7
SP - eabj8301
JO - Science immunology
JF - Science immunology
IS - 70
M1 - abj8301
ER -