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The ESCRT protein CHMP5 escorts αβ T cells through positive selection

Cellular & Molecular Immunology volume 15, pages 654–656 (2018)Cite this article

αβ T lymphocytes are critical for host protection against pathogens and are notable for their recent use as immunotherapeutic agents for the treatment of human cancer. However, their dysfunction is associated with a variety of disease states, including autoimmune and immunodeficient syndromes that frequently result from improper αβ T cell development in the thymus. After thymic egress, mature αβ T cells are activated when their surface T-cell receptor (TCR) engages peptide antigens displayed by major histocompatibility complex (MHC) proteins expressed on antigen-presenting cells. In the thymus, each developing αβ T cell (thymocyte) recombines its TCRβ and TCRα genes in an attempt to assemble and express a unique functional αβ TCR, which is required for survival and development into CD4+CD8+ double-positive (DP) thymocytes. The affinity of the TCR for peptide:MHC displayed by thymic epithelial cells dictates whether the immature αβ T lymphocyte survives and continues differentiating (low affinity directs positive selection) or dies via apoptosis (high affinity triggers negative selection). Altogether, these two checkpoints ensure that the host generates a diverse protective and self-tolerant αβ TCR repertoire. Although it is recognized that the degree and extent of TCR signaling activated by intra-thymic TCR/peptide: MHC interactions directs positive or negative selection, the precise intracellular mechanisms that orchestrate this developmental decision remain enigmatic. In this research highlight, we discuss recent work from Adoro et al. 1 that uncovers an unexpected and essential function of the ESCRT (Endosomal Sorting Complex Required for Transport) protein CHMP5 in mediating thymocyte positive selection.

Prior studies had indicated roles for proteasome-dependent post-translational regulatory mechanisms in TCR signaling and in αβ T cell development.2,3,4 Adoro et al. 1 sought to identify proteins for which the expression in thymocytes is regulated by proteasomal degradation. They found that the CHMP5 protein was stabilized upon treatment with an ubiquitin-dependent proteasome inhibitor. By quantifying Chmp5 transcription and CHMP5 protein levels in thymocytes at specific developmental stages, they discovered that CHMP5 is post-transcriptionally regulated, with the highest CHMP5 protein levels found in post-positively selected thymocytes. As germline CHMP5-deficient mice exhibit early embryonic lethality,5 Adoro et al. 1 generated and analyzed mice with an αβ T lineage-specific deletion of Chmp5 initiating in DP thymocytes prior to positive selection. These mice exhibited lower frequencies and numbers of positively selected thymocytes, disorganized thymic architecture with fragmented medullary regions, and reduced frequencies and numbers of mature αβ T cells. The few αβ T cells that did develop in these mice retained CHMP5 protein expression due to incomplete gene deletion. Using mixed bone marrow chimeric mice, the authors determined that the defect in αβ T cell development is caused by loss of thymocyte-intrinsic CHMP5 function. These observations reveal an essential role (or roles) for CHMP5 in αβ T-cell differentiation at the developmental transition associated with positive selection.

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Acknowledgements

This work was supported by the Immune System Development and Regulation T32-AI055428 (GW) and the National Institutes of Health R01 AI-112621 (CHB).

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  1. Immunology Graduate Group, Perelman School of Medicine, at the University of Pennsylvania, 19104, Philadelphia, PA, USA

    Glendon S Wu & Craig H Bassing

  2. Divsion of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Abramson Family Cancer Research Institute, Perelman School of Medicine, at the University of Pennsylvania, 19104, Philadelphia, PA, USA

    Glendon S Wu & Craig H Bassing

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Correspondence to Craig H Bassing.

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Wu, G.S., Bassing, C.H. The ESCRT protein CHMP5 escorts αβ T cells through positive selection. Cell Mol Immunol 15, 654–656 (2018). https://doi.org/10.1038/cmi.2017.101

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