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  • Review Article
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What rheumatologists need to know about innate lymphocytes

Nature Reviews Rheumatology volume 12, pages 658–668 (2016)Cite this article

Subjects

Key Points

  • Innate lymphocytes can have protective or pathogenic roles in the initiation and maintenance of immune responses

  • Some innate lymphocyte subsets also seem to be involved in autoimmunity

  • The role of innate lymphocytes in autoimmunity can involve protective regulatory functions or proinflammatory cytokine production and cytotoxic tissue damage

  • Innate lymphocytes can also respond to biologic therapies that are used to treat autoimmune diseases

  • Based on current knowledge, innate lymphocyte subsets could be appropriate therapeutic targets in various autoimmune diseases

Abstract

Many rheumatic diseases are characterized by having an autoimmune background. Determining the mechanisms underlying autoimmunity is, therefore, important to further understand these diseases and to inform future lines of research aimed at developing new treatments and cures. As fast responders, innate lymphocytes have protective or pathogenic roles in the initiation as well as the maintenance of immune responses in general, and they contribute to tissue homeostasis, among other functions. Innate lymphocytes also seem to be involved in autoimmunity in particular. Since 2010, accumulating evidence clearly shows that different populations of innate lymphocytes have roles in responding to antigen-specific autoantibody and autoreactive T cells, thereby amplifying or attenuating disease processes. Cytotoxicity is a cardinal feature of many innate lymphocytes and can contribute to inflammatory tissue damage. Finally, innate lymphocytes can respond to biologic therapies for autoimmune diseases. Consequently, like TNF and other effector molecules, certain innate lymphocyte subsets might be appropriate therapeutic targets to ameliorate various autoimmune diseases. In this Review, we summarize the main characteristics and functions of innate lymphocyte subsets, and describe their roles in autoimmune disease. We also discuss how biologic therapies influence innate lymphocyte function and consider the potential for these cell subsets to act as future therapeutic targets.

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Figure 1: Innate lymphocytes can initiate protective and destructive immune responses.

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Acknowledgements

The authors thank the Manchester Collaborative Centre for Inflammation Research (MCCIR), Institute of Inflammation and Repair, University of Manchester, UK, and other colleagues for stimulating discussions, and they apologize to those whose work was not fully cited. M.A.E. was supported by an unrestricted grant to MCCIR by AstraZeneca and GlaxoSmithKline and by US NIH grant CA170194. G.C.T. is supported by NIH grant AI42269. K.H.G.M. is supported by Science Foundation Ireland grant PI/11/1036. D.E. received support from Scientific Research Flanders (FWO), a concerted research action grant of the Research Council of Ghent University (Belgium), from InterUniversity Attraction Pole (IUAP) grant Devrepair from the Belspo Agency (project P7/07) and from the EU Seventh Framework Programme (EC-GA n° 305266 'MIAMI'). D.E. is a member of a Multidisciplinary Research Platform of Ghent University. B.M. received an MCCIR Clinical Training Fellowship.

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Author notes

  1. mexley@partners.org

  2. mark.exley@manchester.ac.uk

Authors and Affiliations

  1. Manchester Collaborative Centre for Inflammation Research (MCCIR), The University of Manchester, Grafton Street, M13 9NT, Manchester, UK

    Mark A. Exley & Ben Mulhearn

  2. Gastroenterology, Hepatology & Endoscopy, Brigham & Women's Hospital, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Mark A. Exley

  3. Agenus Inc., 3 Forbes Road, Lexington, 02421, Massachusetts, USA

    Mark A. Exley

  4. Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, 02215, Massachusetts, USA

    George C. Tsokos

  5. School of Biochemistry and Immunology, Biomedical Sciences Institute, Trinity College Dublin, 152–160 Pearse Street, 2, Dublin, Ireland

    Kingston H.G. Mills

  6. Department of Rheumatology, Laboratory for Molecular Immunology and Inflammation, University Hospital Ghent, De Pintelaan 185, 0K12B, B-9000, Ghent, Belgium

    Dirk Elewaut

  7. Vlaams Instituut voor Biotechnologie (VIB) Inflammation Research Center, Fiers-Schell-Van Montagu Building, Technologiepark 927, Ghent University, B-9052, Ghent, Belgium

    Dirk Elewaut

  8. Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Oxford Road, M13 9PT, Manchester, UK

    Ben Mulhearn

  9. Central Manchester NHS Foundation Trust, Oxford Road, M13 9WL, Manchester, UK

    Ben Mulhearn

Authors
  1. Mark A. Exley
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Contributions

M.A.E. and B.M. researched data for the article and contributed to discussion of content, writing the article, and reviewing and editing the manuscript before submission. G.C.T. and K.H.G.M. made a substantial contribution to discussion of content, and reviewing and editing the manuscript before submission. D.E. contributed to writing the article, and reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Mark A. Exley.

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Competing interests

M.A.E. declares that he is employed by Agenus Inc., a company developing cancer immunotherapies. B.M., G.C.T., K.H.G.M. and D.E. declare that they have no competing interests.

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Glossary

Regulatory T cells

(Treg cells). Cells characterized by the production of IL-10 as well as high expression of CD25 (IL-2 receptor subunit-α) and the co-stimulation blocker cytotoxic T-lymphocyte antigen 4 (CTLA4). Treg cells keep the immune system in check by inhibiting other cells of the immune system.

T helper type 1

(TH1). A term that is used to refer to an immune response that involves production of cytokines produced by TH1 cells such as IFNγ and TNF, which are important for immunity against intracellular pathogens but also contribute to autoimmunity.

TH17

(T helper type 17). A term that is used to refer to an immune response characterized by the production of cytokines of the IL-17 family. IL-17 is a proinflammatory cytokine produced by TH17 cells, as well as group 3 innate lymphoid cells and γδ T cells.

TH0

(T helper of no type). A terms that used to refer to naive T cells that have not yet encountered their cognate antigen and are able to become an effector or a memory T cell.

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Exley, M., Tsokos, G., Mills, K. et al. What rheumatologists need to know about innate lymphocytes. Nat Rev Rheumatol 12, 658–668 (2016). https://doi.org/10.1038/nrrheum.2016.140

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