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The emerging family of RORγt+ antigen-presenting cells

Nature Reviews Immunology volume 24, pages 64–77 (2024)Cite this article

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Abstract

Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host–microorganism interactions. These RORγt+ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt+ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.

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Fig. 1: A timeline of research leading to the characterization of RORγt+ APCs.
Fig. 2: The phenotype and function of RORγt+ APCs in mice.

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Acknowledgements

The authors thank members of the Abramson, Dobeš and Sonnenberg laboratories for discussions and critical reading of the manuscript. G.F.S. is kindly supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R01AI162936, R37AI174468 and R01CA274534), the NIAID Mucosal Immunology Studies Team (MIST), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, the Cancer Research Institute, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. G.F.S. is a CRI Lloyd J. Old STAR. M.L. is supported by a Crohn’s and Colitis Foundation Research Fellowship Award (#935259). J.A. is kindly supported by the Eugene and Marcia Applebaum Professorial Chair, European Research Council (ERC-2016-CoG-724821), IOCB fellowship for sabbatical visit program (RVO 61388963) and Bill and Marika Glied and Family Fund. J.D. is kindly supported by the Czech Science Foundation JUNIOR STAR grant (21-22435M), Czech Science Foundation grant (22-30879S) and by the Charles University PRIMUS grant (Primus/21/MED/003).

Author information

Author notes

  1. These authors contributed equally: Jakub Abramson, Jan Dobeš, Mengze Lyu, Gregory F. Sonnenberg.

Authors and Affiliations

  1. Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel

    Jakub Abramson

  2. Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic

    Jan Dobeš

  3. Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Mengze Lyu & Gregory F. Sonnenberg

  4. Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Mengze Lyu & Gregory F. Sonnenberg

  5. Department of Microbiology & Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Mengze Lyu & Gregory F. Sonnenberg

Authors
  1. Jakub Abramson
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  2. Jan Dobeš
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  3. Mengze Lyu
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  4. Gregory F. Sonnenberg
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Contributions

All authors are equal contributors and collectively conceived the concepts, wrote the manuscript and prepared the figure drafts.

Corresponding authors

Correspondence to Jakub Abramson or Gregory F. Sonnenberg.

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Nature Reviews Immunology thanks J. Gardner and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Autoimmune regulator

(AIRE). A transcriptional regulator initially reported to be expressed by medullary thymic epithelial cells, where it has a role in central immune tolerance by inducing the expression of tissue-restricted antigens.

Non-professional APCs

A subset of antigen-presenting cells (APCs), such as thymic epithelial cells, endothelial cells and granulocytes, that modulate the quality of the CD4+ T cell response in peripheral tissues through antigen presentation on MHC class II.

Professional APCs

A subset of antigen-presenting cells (APCs), including conventional dendritic cells, macrophages and B cells, that are specialized in activating naive CD4+ T cell responses through phagocytosis of exogenous antigens and through processing and presentation of antigenic peptides on their MHC class II molecules, together with co-stimulatory signals.

RORγt+ APCs

A newly defined family of antigen-presenting cells (APCs) that express retinoic acid receptor-related orphan receptor-γt (RORγt) and can present antigens to CD4+ T cells through MHC class II.

Tissue-restricted antigens

(TRAs). Self-antigens whose coding genes are expressed in less than five different parenchymal tissues (out of approximately 60) based on currently available expression atlases. Expression of these genes may also be restricted to a particular developmental period, be sex specific or be regulated by complex biochemical pathways.

Type 3 immune responses

Type 3 immune responses involve RORγt+ lymphocytes, including T helper 17 cells, that produce the cytokines IL-17 and IL-22 to mediate antimicrobial responses and neutrophil recruitment. Type 3 immune responses are protective in the case of extracellular bacterial or fungal infections but, if dysregulated, can drive chronic inflammation.

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Abramson, J., Dobeš, J., Lyu, M. et al. The emerging family of RORγt+ antigen-presenting cells. Nat Rev Immunol 24, 64–77 (2024). https://doi.org/10.1038/s41577-023-00906-5

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