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  • Review Article
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T cell regeneration after immunological injury

Nature Reviews Immunology volume 21, pages 277–291 (2021)Cite this article

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Abstract

Following periods of haematopoietic cell stress, such as after chemotherapy, radiotherapy, infection and transplantation, patient outcomes are linked to the degree of immune reconstitution, specifically of T cells. Delayed or defective recovery of the T cell pool has significant clinical consequences, including prolonged immunosuppression, poor vaccine responses and increased risks of infections and malignancies. Thus, strategies that restore thymic function and enhance T cell reconstitution can provide considerable benefit to individuals whose immune system has been decimated in various settings. In this Review, we focus on the causes and consequences of impaired adaptive immunity and discuss therapeutic strategies that can recover immune function, with a particular emphasis on approaches that can promote a diverse repertoire of T cells through de novo T cell formation.

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Fig. 1: Overview of the dynamics and determinants of T cell reconstitution after haematopoietic cell transplantation.
Fig. 2: Simplified overview of T cell generation with regenerative strategies after immune injury.

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Acknowledgements

The authors are grateful for support from the US National Cancer Institute (R01-CA228358, R01-CA228308, R01-HL147584, P30-CA008748 Memorial Sloan Kettering Cancer Center Support Grant/Core Grant and Project 2 of P01-CA023766), the US National Heart, Lung, and Blood Institute (R01-HL125571 and R01-HL123340), the US National Institute on Aging (Project 2 of P01-AG052359), the Tri-Institutional Stem Cell Initiative (2016-013) and the US National Institute of Allergy and Infectious Diseases (U01-AI124275) to M.R.M.v.d.B., the Amy Strelzer Manasevit Research Program, the Italian Association for Cancer Research and the Italian Ministry of Health (Ricerca Corrente programme) to E.V. and a Society of Memorial Sloan Kettering Cancer Center Scholars Award to J.J.T. Additional funding was received from The Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program and the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center and Seres Therapeutics.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Enrico Velardi

  2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jennifer J. Tsai & Marcel R. M. van den Brink

  3. Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA

    Jennifer J. Tsai

  4. Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Marcel R. M. van den Brink

  5. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA

    Marcel R. M. van den Brink

Authors
  1. Enrico Velardi
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  2. Jennifer J. Tsai
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  3. Marcel R. M. van den Brink
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Enrico Velardi or Marcel R. M. van den Brink.

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Competing interests

M.R.M.v.d.B. has received research support and stock options from Seres Therapeutics, has received royalties from Wolters Kluwer, has consulted for, received honoraria from or participated in advisory boards for Seres Therapeutics, Jazz Pharmaceuticals, Rheos, Therakos, WindMIL Therapeutics, Amgen, Merck & Co. Inc., Magenta Therapeutics, DKMS Medical Council (board), Forty Seven Inc. (spouse), Pharmacyclics (spouse) and Kite Pharmaceuticals (spouse) and has intellectual property licensing agreements with Seres Therapeutics and Juno Therapeutics. E.V. has acted as a consultant for and received honoraria from Ferring Pharmaceuticals. M.R.M.v.d.B. is an inventor on a patent application (US2015/058095) submitted by Memorial Sloan Kettering Cancer Center. Two provisional patent applications have been filed (US 15/033,178 and US 62/566,897) with E.V. and M.R.M.v.d.B. listed as inventors. J.J.T. declares no competing interests.

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Glossary

Thymic epithelial cells

(TECs). The major component of thymic stroma that supports all stages of thymocyte development. They are further divided into cortical and medullary TECs on the basis of their localization within the thymus and are crucial for the positive and negative selection of thymocytes, respectively.

Graft-versus-host disease

(GVHD). Following allogeneic bone marrow transplantation, donor-derived T cells can be activated by residual host-derived antigen-presenting cells. The resulting T cell reactivity can escalate into the life-threatening condition known as GVHD, which targets mainly the skin, liver and intestines. Acute GVHD is a rapid response against recipient tissues that usually manifests itself within 100 days following haematopoietic cell transplantation, whereas chronic GVHD is reactions that occur after 100 days.

Sepsis

A severe, life-threatening form of infection characterized by systemic inflammatory response with resultant multi-organ failure followed by immunosuppression.

Glucocorticoids

A group of compounds that belong to the corticosteroid family. These compounds can be either naturally produced (hormones) or synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Many synthetic glucocorticoids (for example, dexamethasone) are used in clinical medicine as anti-inflammatory drugs.

Conditioning regimens

Also known as preparative regimens. A combination of chemotherapy, radiotherapy and/or immunosuppressive medications that is designed not only to destroy residual malignant cells but also to provide space for donor stem cell engraftment and to provide immunosuppression to prevent host rejection of the donor stem cells.

TCR excision circles

(TRECs). Non-replicative DNA episomes that are normally produced as by-products during T cell receptor (TCR) rearrangement in thymocytes. They are therefore expressed only in T cells of thymic origin and provide a useful tool to assess thymic function and recovery of the T cell pool.

Common lymphoid progenitors

Progenitors of lymphoid cell lineages, which include B cells, T cells, natural killer cells and innate lymphoid cells. Bone marrow common lymphoid progenitors are defined by their expression of the interleukin-7 receptor, FMS-related tyrosine kinase 3 (FLT3) and KIT, and the absence of all conventional lineage markers.

Innate lymphoid cells

(ILCs). A group of innate immune cells that are lymphoid in morphology and developmental origin but lack properties of adaptive B cells and T cells such as recombined antigen-specific receptors. They function in the regulation of immunity, tissue homeostasis and inflammation in response to cytokine stimulation.

Allogeneic HCT

Transplantation approach involving transfer of haematopoietic cells from a healthy donor to a patient after conditioning with high-intensity chemotherapy or irradiation. This approach can be used to treat either malignant or non-malignant disorders. Mismatches between the histocompatibility antigens of the donor and the patient can lead to adverse events, such as rejection of the transplanted graft or pathological immune responses to normal tissues in the patient.

Cytokine receptor common subunit-γ

A chain common to type I cytokine receptors. It was first discovered as the γ-chain of the interleukin-2 (IL-2) receptor and was subsequently shown also to be present in the receptors for IL-4, IL-7, IL-9, IL-15 and IL-21. Gene mutations affecting this γ-chain in humans result in absence of T cells and natural killer cells, a condition termed X-linked severe combined immunodeficiency.

Recent thymic emigrants

(RTEs). Semimature T cells that have left the thymus but have yet to undergo the final stages of maturation. Typically a window of around 2 weeks after thymic maturation is used to differentiate between RTEs and fully mature T cells.

Lymphoid tissue inducer (LTi) cells

Cells that are present in developing lymph nodes, Peyer’s patches and nasopharynx-associated lymphoid tissue. They are required for the development of these lymphoid organs and are characterized by expression of the transcription factor RORγt, interleukin-7 receptor-α and lymphotoxin-α1β2.

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Velardi, E., Tsai, J.J. & van den Brink, M.R.M. T cell regeneration after immunological injury. Nat Rev Immunol 21, 277–291 (2021). https://doi.org/10.1038/s41577-020-00457-z

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