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T Cell Regeneration After Immunological Injury

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T Cell Regeneration After Immunological Injury REVIEWS T cell regeneration after immunological injury Enrico Velardi 1 ✉ , Jennifer J. Tsai 2,3 and Marcel R. M. van den Brink 2,4,5 ✉ 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. Thymic epithelial cells Recovery of immunocompetence after periods of hae- progressive involution of thymic tissue during ageing (TECs). The major component matopoietic stress or injury is crucial not only for effi- leads to a decline in T cell output and T cell senescence of thymic stroma that supports cient responses against pathogens and tumour antigens with restricted TCR repertoire diversity and impaired all stages of thymocyte but also for optimal responses to immunotherapy for immune responses. development. They are further divided into cortical cancer. In contrast to the early recovery of innate cells, Thymic damage and impaired T cell reconstitu- 7 and medullary TECs on the including neutrophils, natural killer (NK) cells and tion are particularly detrimental in HCT recipients . basis of their localization monocytes, adaptive immune cells, in particular T cells, Defective quantitative and functional recovery of T cells, within the thymus and are recover at a much slower pace and are particularly sen- in particular of CD4+ T cells8–11, has been directly linked crucial for the positive and sitive to negative insults caused by infections or cytore- to increased risks of opportunistic infections9,12, malig- negative selection of 13 14,15 thymocytes, respectively. ductive chemotherapy and radiotherapy. Constrictions nant relapse and overall adverse clinical outcomes . in the diversity of the T cell pool have been associated Defective T cell responses are a clinical hurdle not only 1Department of Pediatric with impaired immune responses to several antigens1–3 for patients receiving HCT but also for patients receiving Hematology and Oncology, and adverse clinical outcomes in patients receiving other modalities of cancer immunotherapy, including Bambino Gesù Children’s 4,5 Hospital, IRCCS, Rome, Italy. haematopoietic cell transplantation (HCT) . immune checkpoint inhibitors, that exert their antitu- The capacity of T cells to mount and maintain effec- mour effects primarily through the activation of T cell 2Department of Medicine, Memorial Sloan Kettering tive responses to a wide variety of antigens depends effector function. Although the prognostic significance Cancer Center, New York, on a large repertoire of unique T cell receptors (TCRs) of this association has still to be further characterized NY, USA. generated in the thymus during the process of T cell in larger studies, a highly diverse pool of T cells before 3Department of Medicine, development. This process is dependent on crosstalk therapy correlates with improved outcome after immune State University of New York, between bone marrow (BM)-derived T cell progeni- checkpoint blockade therapy16–19. Thus, there is consid- Downstate Medical Center, tors and the supportive thymic stromal microenviron- erable interest in developing approaches to evaluate the Brooklyn, NY, USA. ment, which primarily consists of thymic epithelial cells quantity and quality of T cells before and during differ- 4Department of Immunology, Memorial Sloan Kettering (TECs), endothelial cells, mesenchymal stromal cells, ent forms of immunotherapy to guide treatment direc- 6 Cancer Center, New York, dendritic cells and macrophages . Although, for exam- tions, monitor immune responses and ultimately identify NY, USA. ple, T cell proliferation, driven by interleukin-7 (IL-7) functional biomarkers to predict clinical outcomes20. 5Department of Microbiology and IL-15, in response to lymphopenic conditions can In this Review, we highlight the primary causes of and Immunology, Weill Cornell contribute to numerical reconstitution of T cells, com- impaired immune function, with special emphasis on Medical College, New York, plete long-term recovery of a diverse and functional HCT recipients, and discuss regenerative approaches that NY, USA. T cell pool requires reactivation of thymic function and have been clinically translated to facilitate the recovery of ✉e-mail: enrico.velardi@ (Fig. 1) opbg.net; vandenbm@ de novo T cell generation . However, the thymus adaptive immune function. We also provide an update on mskcc.org is sensitive to various injuries, such as those caused emerging new immune-boosting approaches that have https://doi.org/10.1038/ by cytoreductive treatments, infection, septic shock demonstrated promising regenerative properties in pre- s41577-020-00457-z and graft-versus-host disease (GVHD). Furthermore, clinical models. We focus on approaches that can broaden NATURE REVIEWS | IMMUNOLOGY VOLUME 21 | MAY 2021 | 277 REVIEWS Post-transplant factors Pretransplant Conditioning GVHD, infections, immunosuppressive therapies factors Donor • Patient age T cells • Prior treatments + • Disease • Monocytes • CD8 T cells • Donor source • Neutrophils • B cells • HLA disparity • NK cells HCT CD4+ T cells • HSC dose • Graft manipulation • Conditioning 0 30 days 100 days 6 months 2 years Immune recovery Incomplete T cell recovery Optimal T cell reconstitution • Homeostatic expansion • De novo T cell formation • Reduced antigen specificity • Increased TCR repertoire diversity and antigen specificity IL-7, IL-15 Reactivation of thymic function Immune-boosting strategies Fig. 1 | Overview of the dynamics and determinants of T cell reconstitution after haematopoietic cell transplantation. In the first period following haematopoietic cell transplantation (HCT), immune cells follow a predictable course of reconstitution. In contrast to the relatively early recovery of innate immune cells, recipients of HCT experience prolonged deficiencies in T cells and B cells, which can take more than 2 years to fully recover. This is particularly evident in adult patients, whose thymic function is lessened owing to age-related thymic involution. The ‘first wave’ of T cells after HCT comprises donor T cells that undergo lymphopenia-induced homeostatic proliferation and alloactivation. This results in polyclonal T cells with a restricted T cell receptor (TCR) repertoire and limited antigen specificity, or with alloreactivity Graft-versus-host disease causing graft-versus-host disease (GVHD). Overall, the incomplete recovery of the T cell pool has been directly linked to (GVHD). Following allogeneic increased risks of infection, malignancy relapse and adverse clinical outcomes. Optimal and complete T cell reconstitution bone marrow transplantation, requires the regeneration of thymic function and the reactivation of endogenous T cell development. This allows the donor-derived T cells can generation of a new T cell pool with broad TCR diversity. Multiple pretransplant and post-transplant factors influence be activated by residual the overall process of T cell reconstitution. HSC, haematopoietic stem cell; IL, interleukin; NK, natural killer. host-derived antigen-presenting cells. The resulting T cell reactivity can escalate into the life-threatening condition the diversity of the T cell pool through the restoration of stromal compartments can both be directly targeted in known as GVHD, which targets de novo T cell formation in the thymus and discuss the viral and parasitic infections. CD4+CD8+ double-positive mainly the skin, liver and intestines. Acute GVHD implications for other cancer immunotherapies. While (DP) thymocytes and their immediate precursors hi low + is a rapid response against this Review primarily concentrates on T cell immunity, CD24 CD3 CD8 single-positive thymocytes are par- recipient tissues that usually a brief summary of the B cell defects associated with ticularly vulnerable, whereas mature CD24mid/lowCD8+ manifests itself within 100 days immunological insults is provided in BOx 1. SP cells are the most resistant thymic subsets during following haematopoietic cell infection25,26. Although the precise mechanisms for transplantation, whereas chronic GVHD is reactions that Conditions leading to immune dysfunction infection-induced acute thymic involution remain to be occur after 100 days. Infection. In the healthy state, homeostasis of the immune further elucidated, stress-responsive hormones (such as system relies on a fine balance between cell production glucocorticoids), pro-inflammatory mediators (such Sepsis and cell death. During an infection, this dynamic equi- as interferon-γ (IFNγ) and tumour necrosis factor A severe, life-threatening form of infection characterized librium is altered to ensure pathogen clearance without (TNF)) and apoptosis pathways (such as those medi- by systemic inflammatory unrestrained immune responses. Haematopoietic stem ated by BAX, BCL-2, JUN amino-terminal
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