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  • Review Article
  • Published:

Regulatory T cell memory

Nature Reviews Immunology volume 16, pages 90–101 (2016)Cite this article

Subjects

Key Points

  • Memory lymphocytes have an indispensable role in eradicating pathogens. They mediate their effects by responding more robustly with repeated infections.

  • Studies of immune memory have primarily focused on effector B cells and T cells. However, recent work has identified persistently expanded populations of antigen-specific regulatory T (TReg) cells.

  • It is hypothesized that memory TReg cells are generated to regulate memory effector responses and to mitigate collateral damage to tissues in the face of these robust immune reactions.

  • Memory TReg cells have been shown to have major roles in animal models of autoimmunity, antimicrobial host defence and maternal–fetal tolerance. In addition, there is evidence that these cells exist in humans.

  • Lack of definitive markers has hampered the phenotypic and the functional characterization of memory TReg cells. Comprehensive transcriptional profiling and detailed examination of epigenetic and metabolic signatures will be essential in defining the functional role that memory TReg cells have in both health and disease.

Abstract

Memory for antigen is a defining feature of adaptive immunity. Antigen-specific lymphocyte populations show an increase in number and function after antigen encounter and more rapidly re-expand upon subsequent antigen exposure. Studies of immune memory have primarily focused on effector B cells and T cells with microbial specificity, using prime–challenge models of infection. However, recent work has also identified persistently expanded populations of antigen-specific regulatory T cells that protect against aberrant immune responses. In this Review, we consider the parallels between memory effector T cells and memory regulatory T cells, along with the functional implications of regulatory memory in autoimmunity, antimicrobial host defence and maternal–fetal tolerance. In addition, we discuss emerging evidence for regulatory T cell memory in humans and key unanswered questions in this rapidly evolving field.

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Figure 1: Life cycle of regulatory and conventional CD4+ T cells.
Figure 2: Mouse models for studying memory TReg cells.
Figure 3: Predicted model for the relationship between resting, effector and memory TReg cells.

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Acknowledgements

S.S.W. is supported by the NIH through awards R01AI100934, R01AI120202 and R21AI112186, the March of Dimes Foundation and the Investigator in the Pathogenesis of Infectious Disease program from the Burroughs Wellcome Fund. M.D.R. is supported by the NIH through awards DP2AR068130, K08AR062064, R21AR066821 and UM1AI110498, by the Burroughs Wellcome Fund Career Award for Medical Scientists, the Scleroderma Research Foundation, the National Psoriasis Foundation and the Dermatology Foundation Stiefel Scholar Award in Autoimmune &/or Connective Tissue Diseases.

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Authors and Affiliations

  1. Department of Dermatology, University of California San Francisco, San Francisco, 94143, California, USA

    Michael D. Rosenblum

  2. Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital, Cincinnati, 45229, Ohio, USA

    Sing Sing Way

  3. Department of Pathology, University of California San Francisco, San Francisco, 94143, California, USA

    Abul K. Abbas

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Correspondence to Abul K. Abbas.

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Glossary

Memory TReg cells

Previously activated regulatory T (TReg) cells that persist in the absence of antigen expression or in the presence of intermittent low-level antigen expression. It is currently unknown whether central memory T cell, effector memory T cell or tissue-resident memory T cell subsets of memory TReg cells exist.

Central memory T cells

(TCM cells). Generated in secondary lymphoid tissues and reside in secondary lymphoid tissues in the absence of antigen.

Effector memory T cells

(TEM cells). Generated in secondary lymphoid tissues and recirculate between blood and non-lymphoid tissues in the absence of antigen.

Tissue-resident memory T cells

(TRM cells). Generated in non-lymphoid tissues and stably reside in these tissues in the absence of antigen.

Tissue-restricted self antigens

Self antigens that are expressed in specific tissues during defined periods of time. Hair follicle-associated antigens are an example of tissue-restricted self antigens in skin.

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Rosenblum, M., Way, S. & Abbas, A. Regulatory T cell memory. Nat Rev Immunol 16, 90–101 (2016). https://doi.org/10.1038/nri.2015.1

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