Circulating innate lymphoid cells (cILCs): Unconventional lymphocytes with hidden talents

Innate lymphoid cells (ILCs) are a group of lymphocytes that are devoid of antigen-specific receptors and are mainly found in tissues. The subtypes ILC1, 2, and 3 mirror T-cell functionality in terms of cytokine production and expression of key transcription factors. Although the majority of ILCs are found in tissue (tILCs), they have also been described within the circulation (cILCs). As a result of their better accessibility and putative prognostic value, human cILCs are getting more and more attention in clinical research. However, cILCs are in many aspects functionally distinct from their tILC counterparts. In fact, from the 3 ILC subsets found within the circulation, only for cILC2s could a clear functional correspondence to their tissue counterparts be established. Indeed, cILC2s are emerging as a major driver of allergic reactions with a particular role in asthma. In contrast, recent studies revealed that cILC1s and cILC3s are predominantly in an immature state and constitute progenitors for natural killer cells and ILCs, respectively. We provide an overview about the phenotype and function of the different cILC subtypes compared to tILCs in health and disease, including transcriptomic signatures, frequency dynamics, and potential clinical value. Furthermore, we will highlight the dynamics of the NKp44+ ILC3 subset, which emerges as prognostic marker in peripheral blood for inflammatory bowel disease and leukemia. Innate lymphoid cells (ILCs) are a group of lymphocytes that are devoid of antigen-specific receptors and are mainly found in tissues. The subtypes ILC1, 2, and 3 mirror T-cell functionality in terms of cytokine production and expression of key transcription factors. Although the majority of ILCs are found in tissue (tILCs), they have also been described within the circulation (cILCs). As a result of their better accessibility and putative prognostic value, human cILCs are getting more and more attention in clinical research. However, cILCs are in many aspects functionally distinct from their tILC counterparts. In fact, from the 3 ILC subsets found within the circulation, only for cILC2s could a clear functional correspondence to their tissue counterparts be established. Indeed, cILC2s are emerging as a major driver of allergic reactions with a particular role in asthma. In contrast, recent studies revealed that cILC1s and cILC3s are predominantly in an immature state and constitute progenitors for natural killer cells and ILCs, respectively. We provide an overview about the phenotype and function of the different cILC subtypes compared to tILCs in health and disease, including transcriptomic signatures, frequency dynamics, and potential clinical value. Furthermore, we will highlight the dynamics of the NKp44+ ILC3 subset, which emerges as prognostic marker in peripheral blood for inflammatory bowel disease and leukemia. The immune system consists of a plethora of different immune cells belonging either to the innate or adaptive branch, where each immune cell population has distinct functionality and widely different cell frequencies. Within the lymphoid lineage, CD3+ T cells, CD19+ B cells, and CD94+ natural killer (NK) cells account for over 95% of all circulating lymphocytes.1Apoil P.A. Puissant-Lubrano B. Congy-Jolivet N. Peres M. Tkaczuk J. Roubinet F. et al.Reference values for T, B and NK human lymphocyte subpopulations in adults.Data Brief. 2017; 12: 400-404Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar,2Kokuina E. Breff-Fonseca M.C. Villegas-Valverde C.A. Mora-Díaz I. Normal values of T, B and NK lymphocyte subpopulations in peripheral blood of healthy Cuban adults.MEDICC Rev. 2019; 21: 16-21PubMed Google Scholar In addition, within the last 2 decades, several rare innate immune cell populations were discovered, which lack the abovementioned lineage defining cell surface receptors and express the IL-7 receptor (IL-7R, CD127). These CD127-expressing cells have been collectively named innate lymphoid cells (ILCs) and comprise 3 phenotypically and functionally different subsets: ILC1, ILC2, and ILC3. Each ILC subset has been described to mirror functionality of established CD4+ T helper cell subsets3Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1940) Google Scholar: ILC1s secrete IFN-γ and express the transcription factor (TF) T-bet mirroring TH1 functionality,4Bernink J.H. Peters C.P. Munneke M. te Velde A.A. Meijer S.L. Weijer K. et al.Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues.Nat Immunol. 2013; 14: 221-229Crossref PubMed Scopus (826) Google Scholar ILC2s secrete IL-5, IL-13, as well as some IL-4 and express the TF GATA-3 similar to TH2 cells,5Mjösberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25– and IL-33–responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055Crossref PubMed Scopus (967) Google Scholar and ILC3s have been divided into 2 subsets according to their NKp44 expression secreting IL-22 (NKp44+) or IL-17A/IL-17F (NKp44−).6Hoorweg K. Peters C.P. Cornelissen F. Aparicio-Domingo P. Papazian N. Kazemier G. et al.Functional differences between human NKp44− and NKp44+ RORC+ innate lymphoid cells.Front Immunol. 2012; 3: 72Crossref PubMed Scopus (144) Google Scholar,7Marquardt N. Ivarsson M.A. Sundström E. Åkesson E. Martini E. Eidsmo L. et al.Fetal CD103+ IL-17–producing group 3 innate lymphoid cells represent the dominant lymphocyte subset in human amniotic fluid.J Immunol. 2016; 197: 3069-3075Crossref PubMed Scopus (0) Google Scholar The 2 ILC3 subsets express the TF RorγT, reminiscent of TH17 cells.6Hoorweg K. Peters C.P. Cornelissen F. Aparicio-Domingo P. Papazian N. Kazemier G. et al.Functional differences between human NKp44− and NKp44+ RORC+ innate lymphoid cells.Front Immunol. 2012; 3: 72Crossref PubMed Scopus (144) Google Scholar,8Cella M. Fuchs A. Vermi W. Facchetti F. Otero K. Lennerz J.K.M. et al.A human NK cell subset provides an innate source of IL-22 for mucosal immunity.Nature. 2009; 457: 722-725Crossref PubMed Scopus (0) Google Scholar In humans, ILCs are readily distinguished by flow cytometry on the basis of c-Kit (CD117) and CRTH2 (CD294) expression within the lineage-negative (Lin−) fraction as ILC1 (CD117−CRTH2−), ILC2 (CD117+/−CRTH2+), or ILC3 (CD117+CRTH2−).9Bianca Bennstein S. Riccarda Manser A. Weinhold S. Scherenschlich N. Uhrberg M. OMIP-055: characterization of human innate lymphoid cells from neonatal and peripheral blood.Cytometry A. 2019; 0: 427-430Crossref Scopus (15) Google Scholar, 10Del Zotto G. Vacca P. Moretta L. Quatrini L. CPHEN-15: comprehensive phenotyping of human peripheral blood helper-ILCs by flow cytometry.Cytometry A. 2023; 103: 378-382Crossref Scopus (2) Google Scholar, 11Krabbendam L. Nagasawa M. Spits H. Bal S.M. Isolation of human innate lymphoid cells.Curr Protoc Immunol. 2018; 122e55Crossref Scopus (17) Google Scholar Groundbreaking studies focusing mostly on murine and to some extent on human tissue samples have described ILCs to be vital for tissue homeostasis and mucosal barrier integrity.12Vivier E. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. et al.Innate lymphoid cells: 10 years on.Cell. 2018; 174: 1054-1066Abstract Full Text Full Text PDF PubMed Scopus (1397) Google Scholar,13Mjösberg J. Spits H. Human innate lymphoid cells.J Allergy Clin Immunol. 2016; 138: 1265-1276Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar In particular, the NKp44+ ILC3 subset has been shown to be important for maintaining homeostasis within the gastrointestinal (GI) tract by their secretion of IL-22 after exposition to pathogens and other danger signals, but also commensal bacteria and food components.14Bennstein S.B. Uhrberg M. Biology and therapeutic potential of human innate lymphoid cells.FEBS J. 2022; 289: 3967-3981Crossref Scopus (10) Google Scholar,15Konya V. Mjösberg J. Innate lymphoid cells in graft-versus-host disease.Am J Transpl. 2015; 15: 2795-2801Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Hence, therapeutic applications using human ILCs for adoptive cell transfer could be envisioned and might become novel options for treatment of conditions such as inflammatory bowel disease (IBD). To exploit ILCs for cell-based immunotherapy, they need to be isolated, enriched, and, if applicable, modified in vitro. The most accessible source for human immune cells is blood—either peripheral blood (PB) or umbilical cord blood (CB). However, while effector T, B, and NK cells can be readily isolated from the circulation, recent studies on human circulating ILCs (cILCs) have highlighted that, except for cILC2s, cILCs differ greatly from their tissue counterparts (tILCs) at the functional and transcriptional level.16Bennstein S.B. Weinhold S. Manser A.R. Scherenschlich N. Noll A. Raba K. et al.Umbilical cord blood–derived ILC1-like cells constitute a novel precursor for mature KIR+NKG2A− NK cells.eLife. 2020; 9e55232Crossref Scopus (24) Google Scholar, 17Lim A.I. Li Y. Lopez-Lastra S. Stadhouders R. Paul F. Casrouge A. et al.Systemic human ILC precursors provide a substrate for tissue ILC differentiation.Cell. 2017; 168: 1086-1100.e10Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 18Bennstein S.B. Scherenschlich N. Weinhold S. Manser A.R. Noll A. Raba K. et al.Transcriptional and functional characterization of neonatal circulating ILCs.Stem Cells Transl Med. 2021; 10: 867-882Crossref Scopus (14) Google Scholar Therefore, depending on the human ILC subset of interest, effector cILCs mirroring their tissue-resident counterparts cannot be directly isolated from blood. To solve this problem, alternative approaches to generate human effector ILCs in vitro for potential clinical use have been described.19Bennstein S.B. Weinhold S. Degistirici Ö. Oostendorp R.A.J. Raba K. Kögler G. et al.Efficient in vitro generation of IL-22–secreting ILC3 from CD34+ hematopoietic progenitors in a human mesenchymal stem cell niche.Front Immunol. 2021; 12Google Scholar, 20Ising R. Weinhold S. Bennstein S.B. Zimmermann A. Degistirici Ö. Kögler G. et al.HCMV infection in a mesenchymal stem cell niche: differential impact on the development of NK cells versus ILC3.J Clin Med. 2019; 9: 10Crossref Scopus (8) Google Scholar, 21Hernández D.C. Juelke K. Müller N.C. Durek P. Ugursu B. Mashreghi M.-F. et al.An in vitro platform supports generation of human innate lymphoid cells from CD34+ hematopoietic progenitors that recapitulate ex vivo identity.Immunity. 2021; 54: 2417-2432.e5Abstract Full Text Full Text PDF PubMed Google Scholar, 22Van der Meer J.M.R. Bulder I. Kuijk C. Kleijer M. Verheij M.W. Omar S.Z. et al.Generation of human ILC3 from allogeneic and autologous CD34+ hematopoietic progenitors toward adoptive transfer.Cytotherapy. 2024; 26: 136-144Abstract Full Text Full Text PDF Google Scholar The therapeutic value of human cILCs is so far largely unexplored, but an increasing number of studies are focusing on human cILCs in health and disease. Their ready accessibility in PB as well as CB makes them attractive candidates for novel therapeutic applications. Here we hope to shed light on the functionality, biology, and potential clinical value of human cILCs, as well as to define their distinguishing features from human and mouse tILCs. Frequencies and total cell counts of cILCs are generally low, making them rare immune cells. Total cILC frequency (cILC1-3) ranges from 0.1% to 1% of lymphocytes, and cell count ranges from 2 to 45 cells per microliter of blood.16Bennstein S.B. Weinhold S. Manser A.R. Scherenschlich N. Noll A. Raba K. et al.Umbilical cord blood–derived ILC1-like cells constitute a novel precursor for mature KIR+NKG2A− NK cells.eLife. 2020; 9e55232Crossref Scopus (24) Google Scholar,23Uyen Pham T.X. Bennstein S.B. Klumb J. Niehues T. Uhrberg M. Circulating innate lymphoid cells (ILCs) in healthy children: reference values for evaluation of treatment in immunocompromised pediatric patients.J Clin Immunol. 2022; 42: 1405-1408Crossref Scopus (0) Google Scholar,24Vely F. Barlogis V. Vallentin B. Neven B. Piperoglou C. Ebbo M. et al.Evidence of innate lymphoid cell redundancy in humans.Nat Immunol. 2016; 17: 1291-1299Crossref PubMed Scopus (252) Google Scholar Dynamic changes in the frequency of cILCs in general, and cILC subsets in particular, were observed during aging as well as in the context of viral infection, autoimmunity, and cancer (Table I). Genetics, ethnicity, sex, and environmental factors such as exposure to pathogens and diet25Darboe A. Nielsen C.M. Wolf A.-S. Wildfire J. Danso E. Sonko B. et al.Age-related dynamics of circulating innate lymphoid cells in an African population.Front Immunol. 2020; 11: 3070Crossref Scopus (18) Google Scholar, 26Forsberg A. Bengtsson M. Eringfält A. Ernerudh J. Mjösberg J. Jenmalm M.C. GATA binding protein 3+ group 2 innate lymphoid cells are present in cord blood and in higher proportions in male than in female neonates.J Allergy Clin Immunol. 2014; 134: 228-230.e2Abstract Full Text Full Text PDF PubMed Google Scholar, 27Pascal M. Kazakov A. Chevalier G. Dubrule L. Deyrat J. Dupin A. et al.The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding.Mucosal Immunol. 2022; 15: 629-641Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 28Seillet C. Luong K. Tellier J. Jacquelot N. Shen R.D. Hickey P. et al.The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity.Nat Immunol. 2020; 21: 168-177Crossref PubMed Scopus (134) Google Scholar, 29Talbot J. Hahn P. Kroehling L. Nguyen H. Li D. Littman D.R. Feeding-dependent VIP neuron–ILC3 circuit regulates the intestinal barrier.Nature. 2020; 579: 575-580Crossref PubMed Scopus (192) Google Scholar might also play a role, but the individual quantitative contribution of these factors on cILC frequencies is currently unclear.Table IReported frequency changes of cILCs in diseasesType of diseaseDiseaseChange of lymphocytes/CD45 compared to healthy (% change)NKp44+ cILC3sStudyTotal cILC %cILC1scILC2scILC3sAutoimmune diseaseCrohn diseaseNDHLA-DR+ ↑∗Activated phenotype.SLAMF1+ ↑∗Activated phenotype.CD45RA+ ↑∗Activated phenotype.Present48Mazzurana L. Bonfiglio F. Forkel M. D'Amato M. Halfvarson J. Mjösberg J. Crohn's disease is associated with activation of circulating innate lymphoid cells.Inflamm Bowel Dis. 2020; Google ScholarCrohn ulcerative colitis↓→↓↓Present47Creyns B. Jacobs I. Verstockt B. Cremer J. Ballet V. Vandecasteele R. et al.Biological therapy in inflammatory bowel disease patients partly restores intestinal innate lymphoid cell subtype equilibrium.Front Immunol. 2020; 11Google ScholarMultiple sclerosis treated with anti-CD25→→→→ND52Gillard G.O. Saenz S.A. Huss D.J. Fontenot J.D. Circulating innate lymphoid cells are unchanged in response to DAC HYP therapy.J Neuroimmunol. 2016; 294: 41-45Abstract Full Text Full Text PDF PubMed Google ScholarSystemic sclerosisND↑→↓Present45Roan F. Stoklasek T.A. Whalen E. Molitor J.A. Bluestone J.A. Buckner J.H. et al.CD4+ group 1 innate lymphoid cells form a functionally distinct ILC subset that is increased in systemic sclerosis.J Immunol. 2016; 196: 2051-2062Crossref PubMed Google ScholarPsoriasis vulgaris + atherosclerosis/obesity↑↑↑↑ND43Schielke L. Zimmermann N. Hobelsberger S. Steininger J. Strunk A. Blau K. et al.Metabolic syndrome in psoriasis is associated with upregulation of CXCL16 on monocytes and a dysbalance in innate lymphoid cells.Front Immunol. 2022; 13Crossref Scopus (6) Google ScholarPsoriasis vulgarisNDNDNDNDPresent99Teunissen M.B.M. Munneke J.M. Bernink J.H. Spuls P.I. Res P.C.M. te Velde A. et al.Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients.J Invest Dermatol. 2014; 134: 2351-2360Abstract Full Text Full Text PDF PubMed Scopus (266) Google ScholarPsoriasis arthritis↓↓↓↓Absent44Soare A. Weber S. Maul L. Rauber S. Gheorghiu A.M. Luber M. et al.Cutting edge: homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis.J Immunol. 2018; 200: 1249-1254Crossref PubMed Scopus (0) Google ScholarPsoriasis (not specified further)NDNDNDNDPresent100Villanova F. Flutter B. Tosi I. Grys K. Sreeneebus H. Perera G.K. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (320) Google ScholarAtopic dermatitisNDNDNDNDVery low frequencies100Villanova F. Flutter B. Tosi I. Grys K. Sreeneebus H. Perera G.K. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (320) Google ScholarLupus nephritis↓↓→↑ND51Ryu S. Lee E.Y. Kim D.K. Kim Y.S. Chung D.H. Kim J.H. et al.Reduction of circulating innate lymphoid cell progenitors results in impaired cytokine production by innate lymphoid cells in patients with lupus nephritis.Arthritis Res Ther. 2020; 22: 63Crossref PubMed Scopus (0) Google ScholarANCA↓↓↓↓ND49Braudeau C. Amouriaux K. Néel A. Herbreteau G. Salabert N. Rimbert M. et al.Persistent deficiency of circulating mucosal-associated invariant T (MAIT) cells in ANCA-associated vasculitis.J Autoimmun. 2016; 70: 73-79Crossref PubMed Scopus (10) Google ScholarANCA acute phase↑↓↓ND49Braudeau C. Amouriaux K. Néel A. Herbreteau G. Salabert N. Rimbert M. et al.Persistent deficiency of circulating mucosal-associated invariant T (MAIT) cells in ANCA-associated vasculitis.J Autoimmun. 2016; 70: 73-79Crossref PubMed Scopus (10) Google ScholarANCA→→↓→ND50Fazekas B. Moreno-Olivera A. Kelly Y. O'Hara P. Murray S. Kennedy A. et al.Alterations in circulating lymphoid cell populations in systemic small vessel vasculitis are non-specific manifestations of renal injury.Clin Exp Immunol. 2018; 191: 180-188Crossref Scopus (24) Google ScholarRheumatoid arthritisNDNDNDNDPresent105Ren J. Feng Z. Lv Z. Chen X. Li J. Natural killer-22 cells in the synovial fluid of patients with rheumatoid arthritis are an innate source of interleukin 22 and tumor necrosis factor-α.J Rheumatol. 2011; 38: 2112-2118Crossref PubMed Scopus (40) Google ScholarRheumatoid arthritis→↓↑↑ND109Wang T. Rui J. Shan W. Xue F. Feng D. Dong L. et al.Imbalance of Th17, Treg, and helper innate lymphoid cell in the peripheral blood of patients with rheumatoid arthritis.Clin Rheumatol. 2022; 41: 3837-3849Crossref Scopus (16) Google ScholarOLP↑ Highest in erosive OLP↑↓ → (counts)→Present (nonerosive OLP)101Wang Z.M. Zhang J. Wang F. Zhou G. The tipped balance of ILC1/ILC2 in peripheral blood of oral lichen planus is related to inflammatory cytokines.Front Cell Dev Biol. 2021; 9725169Google ScholarAxial spondyloarthritisNDNDNDNDPresent, highest with dyslipidemia102Min H.K. Moon J. Lee S.Y. Lee A.R. Lee C.R. Lee J. et al.Expanded IL-22+ group 3 innate lymphoid cells and role of oxidized LDL-C in the pathogenesis of axial spondyloarthritis with dyslipidaemia.Immune Netw. 2021; 21: e43Crossref Google ScholarPemphigus vulgaris↓↑→↓ND46Zhu Y. Su J. Zhang P. Deng M. Wu R. Liu Y. et al.The dysregulation of circulating innate lymphoid cells is related to autoantibodies in pemphigus vulgaris.Int Immunopharmacol. 2023; 117109921Crossref Scopus (3) Google ScholarAsthma/allergyAsthma (sputum)NDND↑NDND55Miao Q. Wang Y. Liu Y.G. Ren Y.X. Guan H. Li Z. et al.Seasonal variation in circulating group 2 innate lymphoid cells in mugwort-allergic asthmatics during and outside pollen season.Allergy Asthma Clin Immunol. 2018; 14: 6Crossref Scopus (3) Google ScholarAsthma (sputum)↑↑↑↑Present54Kim J. Chang Y. Bae B. Sohn K.H. Cho S.H. Chung D.H. et al.Innate immune crosstalk in asthmatic airways: innate lymphoid cells coordinate polarization of lung macrophages.J Allergy Clin Immunol. 2019; 143: 1769-1782.e11Abstract Full Text Full Text PDF PubMed Google ScholarSmokers vs nonsmokers sputum→→→↑Present110Ham J. Kim J. Sohn K.H. Park I.W. Choi B.W. Chung D.H. et al.Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells.Nat Commun. 2022; 13: 3852Crossref Scopus (14) Google ScholarSmokers vs nonsmokers blood→→→→ND110Ham J. Kim J. Sohn K.H. Park I.W. Choi B.W. Chung D.H. et al.Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells.Nat Commun. 2022; 13: 3852Crossref Scopus (14) Google ScholarViral infectionCOVID-19↓→→, CD117+↓, CD117− ↑→ND111Forte D. Pellegrino R.M. Trabanelli S. Tonetti T. Ricci F. Cenerenti M. et al.Circulating extracellular particles from severe COVID-19 patients show altered profiling and innate lymphoid cell–modulating ability.Front Immunol. 2023; 14Crossref Scopus (2) Google ScholarCOVID-19 moderate↓ NS→↑↓ND30García M. Kokkinou E. Carrasco García A. Parrot T. Palma Medina L.M. Maleki K.T. et al.Innate lymphoid cell composition associates with COVID-19 disease severity.Clin Transl Immunol. 2020; 9e1224Crossref Scopus (54) Google ScholarCOVID-19 severe↓→→↓ND30García M. Kokkinou E. Carrasco García A. Parrot T. Palma Medina L.M. Maleki K.T. et al.Innate lymphoid cell composition associates with COVID-19 disease severity.Clin Transl Immunol. 2020; 9e1224Crossref Scopus (54) Google ScholarAcute HIV↓↓↓↓Absent31Kløverpris H.N. Kazer S.W. Mjösberg J. Mabuka J.M. Wellmann A. Ndhlovu Z. et al.Innate lymphoid cells are depleted irreversibly during acute HIV-1 infection in the absence of viral suppression.Immunity. 2016; 44: 391-405Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar,32Nabatanzi R. Cose S. Joloba M. Jones S.R. Nakanjako D. Effects of HIV infection and ART on phenotype and function of circulating monocytes, natural killer, and innate lymphoid cells.AIDS Res Ther. 2018; 15: 7Crossref PubMed Scopus (33) Google ScholarTumorAML↓→↓→Present56Munneke J.M. Björklund A.T. Mjösberg J.M. Garming-Legert K. Bernink J.H. Blom B. et al.Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease.Blood. 2014; 124: 812-821Crossref PubMed Scopus (191) Google ScholarAfter HSCT↓↓↓↓Present56Munneke J.M. Björklund A.T. Mjösberg J.M. Garming-Legert K. Bernink J.H. Blom B. et al.Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease.Blood. 2014; 124: 812-821Crossref PubMed Scopus (191) Google ScholarMelanomaND→→→ND57Rethacker L. Roelens M. Bejar C. Maubec E. Moins-Teisserenc H. Caignard A. Specific patterns of blood ILCs in metastatic melanoma patients and their modulations in response to immunotherapy.Cancers. 2021; 13: 1446Crossref PubMed Scopus (0) Google ScholarMelanoma + ipilimumabND↓↓→ND57Rethacker L. Roelens M. Bejar C. Maubec E. Moins-Teisserenc H. Caignard A. Specific patterns of blood ILCs in metastatic melanoma patients and their modulations in response to immunotherapy.Cancers. 2021; 13: 1446Crossref PubMed Scopus (0) Google ScholarOther diseasesSeptic shock (cell count)→↓↑↑ND53Carvelli J. Piperoglou C. Bourenne J. Farnarier C. Banzet N. Demerlé C. et al.Imbalance of circulating innate lymphoid cell subpopulations in patients with septic shock.Front Immunol. 2019; 10Google ScholarArrows indicate ↓ reduced, ↑ increased, and → unchanged compared to healthy controls; ND, not determined or reported; NS, not significant; and OLP, oral lichen planus.∗ Activated phenotype. Open table in a new tab Arrows indicate ↓ reduced, ↑ increased, and → unchanged compared to healthy controls; ND, not determined or reported; NS, not significant; and OLP, oral lichen planus. The frequencies and cell counts of total cILCs are age dependent: cILCs decrease significantly during aging.16Bennstein S.B. Weinhold S. Manser A.R. Scherenschlich N. Noll A. Raba K. et al.Umbilical cord blood–derived ILC1-like cells constitute a novel precursor for mature KIR+NKG2A− NK cells.eLife. 2020; 9e55232Crossref Scopus (24) Google Scholar,23Uyen Pham T.X. Bennstein S.B. Klumb J. Niehues T. Uhrberg M. Circulating innate lymphoid cells (ILCs) in healthy children: reference values for evaluation of treatment in immunocompromised pediatric patients.J Clin Immunol. 2022; 42: 1405-1408Crossref Scopus (0) Google Scholar, 24Vely F. Barlogis V. Vallentin B. Neven B. Piperoglou C. Ebbo M. et al.Evidence of innate lymphoid cell redundancy in humans.Nat Immunol. 2016; 17: 1291-1299Crossref PubMed Scopus (252) Google Scholar, 25Darboe A. Nielsen C.M. Wolf A.-S. Wildfire J. Danso E. Sonko B. et al.Age-related dynamics of circulating innate lymphoid cells in an African population.Front Immunol. 2020; 11: 3070Crossref Scopus (18) Google Scholar The highest frequencies and cell counts of total cILCs have been observed within CB with a subsequent significant decrease in children and adults24Vely F. Barlogis V. Vallentin B. Neven B. Piperoglou C. Ebbo M. et al.Evidence of innate lymphoid cell redundancy in humans.Nat Immunol. 2016; 17: 1291-1299Crossref PubMed Scopus (252) Google Scholar and a further decrease in elderly adults (>63 years).16Bennstein S.B. Weinhold S. Manser A.R. Scherenschlich N. Noll A. Raba K. et al.Umbilical cord blood–derived ILC1-like cells constitute a novel precursor for mature KIR+NKG2A− NK cells.eLife. 2020; 9e55232Crossref Scopus (24) Google Scholar In a detailed analysis of a cohort of healthy children aged between 0 to 18 years, we recently observed infants (0-1 years) to show the highest frequencies and cell counts of total cILCs,23Uyen Pham T.X. Bennstein S.B. Klumb J. Niehues T. Uhrberg M. Circulating innate lymphoid cells (ILCs) in healthy children: reference values for evaluation of treatment in immunocompromised pediatric patients.J Clin Immunol. 2022; 42: 1405-1408Crossref Scopus (0) Google Scholar which significantly decreased by age of schoolchildren (6-12 years) and even further in adolescents (13-18 years).23Uyen Pham T.X. Bennstein S.B. Klumb J. Niehues T. Uhrberg M. Circulating innate lymphoid cells (ILCs) in healthy children: reference values for evaluation of treatment in immunocompromised pediatric patients.J Clin Immunol. 2022; 42: 1405-1408Crossref Scopus (0) Google Scholar,25Darboe A. Nielsen C.M. Wolf A.-S. Wildfire J. Danso E. Sonko B. et al.Age-related dynamics of circulating innate lymphoid cells in an African population.Front Immunol. 2020; 11: 3070Crossref Scopus (18) Google Scholar The 3 ILC subsets display different dynamics in terms of frequencies and cell counts, with cILC1s decreasing from neonatal age to adolescents, while cILC2s and cILC3s are decreasing continuously throughout life. When taking into account the gestational age of CB samples, we observed a significant decrease of cILC1s from early term (37 weeks) toward postterm (43 weeks) delivery, shedding some light on fetal development of cILC1s. A similar correlation with gestational age was not observed for cILC2s or cILC3s.16Bennstein S.B. Weinhold S. Manser A.R. Scherenschlich N. Noll A. Raba K. et al.Umbilical cord blood–derived ILC1-like cells constitute a novel precursor for mature KIR+NKG2A− NK cells.eLife. 2020; 9e55232Crossref Scopus (24) Google Scholar Furthermore, during childhood, cILC1 counts and frequencies were highest in infants (0-1 years) and decreased further in each subsequent age group until adolescence. The cILC1 decrease was also observed in PB and pertained to all cILC1 subsets defined by expression of CD5 and CD161.23Uyen Pham T.X. Bennstein S.B. Klumb J. Niehues T. Uhrberg M. Circulating innate lymphoid cells (ILCs) in healthy children: reference values for evaluation of treatment in immunocompromised pediatric patients.J Clin Immunol. 2022; 42: 1405-1408Crossref Scopus (0) Google Scholar While cILC2s showed a decreasing trend from toddlers (2-5 years) to schoolchildren (6-12 years), cILC3s decreased between schoolchildren and adolescents.23Uyen Pham T.X. Bennstein S.B. Klumb J. Niehues T. Uhrberg M. 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