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Revealing the identity of regulatory T-cell-suppressed self-reactive CD4+ T cells

Cellular & Molecular Immunology volume 20, pages 1093–1094 (2023)Cite this article

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A recent study published in Nature Immunology by Peter Savage and colleagues sought to characterize regulatory T-cell (Treg)-suppressed self-reactive CD4+ T cells using an elegant system combining the depletion of Tregs with T-cell receptor (TCR) sequencing of expanded conventional CD4+ T-cell clones. By tracking the fate of T cells engineered to express the identified TCRs, Lee et al. discovered a ‘new’ subpopulation of CD4+ T cells bearing antigen receptors with high levels of self-reactivity that take on a T follicular helper (TFH)-like phenotype in the periphery in the absence of immune challenge [1].

Antigen-specific αβTCRs are generated through the somatic recombination of V(D)J gene segments during thymic development, giving rise to T cells that can recognize an enormously diverse set of peptides presented by major histocompatibility complex (pMHC) molecules. A risk of this process is that it can also lead to the generation of potentially highly self-reactive TCRs. T cells with TCRs with high affinity for self-pMHC molecules are purged in the thymus by clonal deletion, a key tolerance mechanism that prevents autoimmunity. However, this process is incomplete, and highly self-reactive T cells can escape negative selection and join the peripheral naive T-cell pool. Indeed, while the naive CD4+ T-cell pool is heterogeneous with regard to an individual T cell’s reactivity for self-pMHC molecules, the distribution of T cells with differing strengths of self-reactivity leaving the thymus is skewed toward those with relatively higher self-pMHC binding strengths [2]. A subset of these highly self-reactive CD4+ T cells in the periphery are deleted, some become functionally anergic, and others differentiate into Tregs, which go on to play an important role in peripheral tolerance, holding other CD4+ T cells with potentially dangerous levels of self-reactivity in check [3]. What is the fate of these Treg-suppressed self-reactive cells?

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Authors and Affiliations

  1. Department of Physiology and McGill Research Centre on Complex Traits, McGill University, Montreal, QC, Canada

    Judith N. Mandl

  2. Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada

    Heather J. Melichar

  3. Department of Medicine, Université de Montréal, Montreal, QC, Canada

    Heather J. Melichar

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  1. Judith N. Mandl
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  2. Heather J. Melichar
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Correspondence to Judith N. Mandl or Heather J. Melichar.

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Mandl, J.N., Melichar, H.J. Revealing the identity of regulatory T-cell-suppressed self-reactive CD4+ T cells. Cell Mol Immunol 20, 1093–1094 (2023). https://doi.org/10.1038/s41423-023-01021-0

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