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      A Human Lin CD123 + CD127 low Population Endowed with ILC Features and Migratory Capabilities Contributes to Immunopathological Hallmarks of Psoriasis

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          Abstract

          Innate lymphoid cells (ILC) are members of a heterogeneous family with a lymphoid origin that mimics the T helper (Th) cytokine profile. ILC are involved in early effector cytokine-mediated responses during infections in peripheral tissues. ILC also play an important role in chronic skin inflammatory diseases, including psoriasis. Although classical ILC express CD127, it has been recently reported that the presence of non-classical CD127 ILC populations and an early ILC precursor (EILP) CD127 low. ILC development has predominately been investigated in mouse models. However, in humans, different transcription factors have been described for ILC identification. NFIL3 (nuclear factor, IL-3 regulated) is crucial for ILC development in response to IL-7. CD123 (IL-3Rα) is usually used to exclude basophils during ILC identification, however, it is unknown if in response to IL-3, NFIL3 could be relevant to induce ILC features in Lin CD123 + populations in addition, is also unknown whether peripheral blood (PB) population with ILC features may have skin-homing potential to participate in skin inflammatory chronic diseases. Here, we report a Lin CD123 + CD127 low CD7 + CLA + population that share some phenotypic properties with basophils, but expresses several transcription factors for ILC commitment such as inhibitor of DNA binding 2 (Id2), NFIL3, promyelocytic leukemia zinc finger (PLZF), thymocyte selection-associated high-mobility group box protein (TOX), and T cell factor-1 (TCF-1). In addition, this population expresses different ILC markers: CD132, CD90, CD161, α4 integrin, c-Kit, CRTH2, AhR, and IL-23R. IL-3 prevents apoptosis and increases their NFIL3, TOX, and PLZF expression. In PB, the CD123 + CD127 low population is predominantly a conspicuous population that expresses T-bet and RORγt. The Lin CD123 + CD127 low population in PB has a limited Th type cytokine expression and highly expresses IL-8. The Lin CD123 + CD127 low population expresses skin-homing receptors (cutaneous lymphocyte antigen and CXCR4) and transmigrates through endothelial cells in response to SDF-1. An equivalent Lin CD123 low population was identified in control skin, which shows a broader phenotypic diversity and cytokine production, including IL-22 and IL-17. Remarkably, the CD123 low population in the lesion and non-lesion skin of psoriasis patients expresses IL-17 and IL-22. Our findings suggest the identification of an alternative Lin CD123 + CD127 low population with ILC features endowed with migratory capabilities that might contribute to immunopathological hallmarks of psoriasis.

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          Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.

          Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.
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            Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.

            Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.
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              The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing.

              Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127(+) ILCs and natural killer (NK) cells. Unbiased transcriptional clustering revealed four distinct populations, corresponding to ILC1 cells, ILC2 cells, ILC3 cells and NK cells, with their respective transcriptomes recapitulating known as well as unknown transcriptional profiles. The single-cell resolution additionally divulged three transcriptionally and functionally diverse subpopulations of ILC3 cells. Our systematic comparison of single-cell transcriptional variation within and between ILC populations provides new insight into ILC biology during homeostasis, with additional implications for dysregulation of the immune system.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/360224
                URI : http://frontiersin.org/people/u/378977
                URI : http://frontiersin.org/people/u/372319
                URI : http://frontiersin.org/people/u/404002
                URI : http://frontiersin.org/people/u/373543
                URI : http://frontiersin.org/people/u/404213
                URI : http://frontiersin.org/people/u/415638
                URI : http://frontiersin.org/people/u/415625
                URI : http://frontiersin.org/people/u/404950
                URI : http://frontiersin.org/people/u/86185
                URI : http://frontiersin.org/people/u/293965
                URI : http://frontiersin.org/people/u/237300
                URI : http://frontiersin.org/people/u/370064
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                02 March 2017
                2017
                : 8
                : 176
                Affiliations
                [1] 1Unidad de Investigación Médica en Inmunoquímica Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social , Mexico City, Mexico
                [2] 2Universidad Nacional Autónoma de México (UNAM) , Mexico City, Mexico
                [3] 3Unidad de Investigación en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional ‘Siglo XXI’ , Mexico City, Mexico
                [4] 4División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM) , Mexico City, Mexico
                [5] 5Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México “Federico Gómez” , Mexico City, Mexico
                [6] 6Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública , Cuernavaca, Morelos, Mexico
                [7] 7Centro Dermatológico “Dr. Ladislao de la Pascua”, Secretaria de Salud de la Ciudad de México , Mexico City, Mexico
                Author notes

                Edited by: Heiko Mühl, Goethe University Frankfurt, Germany

                Reviewed by: Marina Cella, Washington University School of Medicine, USA; Anja Fuchs, Washington University in St. Louis, USA

                *Correspondence: Laura C. Bonifaz, labonifaz@ 123456yahoo.com

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00176
                5332395
                28303135
                0ad0f024-ad28-4cad-ad9e-6fa91740f269
                Copyright © 2017 Mora-Velandia, Castro-Escamilla, Méndez, Aguilar-Flores, Velázquez-Avila, Tussié-Luna, Téllez-Sosa, Maldonado-García, Jurado-Santacruz, Ferat-Osorio, Martínez-Barnetche, Pelayo and Bonifaz.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 August 2016
                : 07 February 2017
                Page count
                Figures: 12, Tables: 0, Equations: 0, References: 66, Pages: 19, Words: 12236
                Funding
                Funded by: Instituto Mexicano del Seguro Social 10.13039/501100004881
                Award ID: R-2008-3601-62
                Categories
                Immunology
                Original Research

                Immunology
                innate lymphoid cells,psoriasis,il-3rα,il-17,sdf-1,cxcr4 axis,skin inflammation
                Immunology
                innate lymphoid cells, psoriasis, il-3rα, il-17, sdf-1, cxcr4 axis, skin inflammation

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