T cell regeneration after immunological injury

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.

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 causing graft-versus-host disease (GVHD). Overall, the incomplete recovery of the T cell pool has been directly linked to increased risks of infection, malignancy relapse and adverse clinical outcomes. Optimal and complete T cell reconstitution requires the regeneration of thymic function and the reactivation of endogenous T cell development. This allows the generation of a new T cell pool with broad TCR diversity. Multiple pretransplant and post-transplant factors influence the overall process of T cell reconstitution. HSC, haematopoietic stem cell; IL, interleukin; NK, natural killer.

Fig. 2. Simplified overview of T cell generation with regenerative strategies after immune injury.

T cell development begins when T cell progenitors, originating from common lymphoid progenitors (CLPs) in the bone marrow, migrate into the thymus and progress through a series of well-characterized developmental steps. Thymocytes go through the double-negative (DN; CD4^–CD8^–) and double-positive (DP; CD4⁺CD8⁺) stages to form single-positive (CD4⁺CD8^– or CD4^–CD8⁺) T cells. During this process, approximately 95% of developing thymocytes produced daily are deleted through β-selection, positive selection and negative selection, resulting in the formation of self-restricted and self-tolerant naive CD4⁺ and CD8⁺ single-positive cells that can exit the thymus and migrate to peripheral lymphoid organs. Approaches to enhance T cell recovery act at multiple levels. Factors and approaches such as interleukin-7 (IL-7), IL-12, IL-15, IL-21, FMS-like tyrosine kinase 3 ligand (FLT3LG), growth hormone (GH), insulin-like growth factor 1 (IGF1), sex steroid ablation (SSA), thymosin-α1, stem cell factor (SCF), administration of precursor T cells (pre-T cells) and delivery of ex vivo-generated thymic epithelial cells (exTECs) primarily promote recovery of the haematopoietic compartment. By contrast, keratinocyte growth factor (KGF), IL-22, receptor activator of nuclear factor-κB ligand (RANKL), IGF1, lymphotoxin-α (LTα) and bone morphogenetic protein 4 (BMP4) produced by ex vivo-generated endothelial cells (exECs) enhance reconstitution of the thymic stromal compartment. Question marks denote approaches where the effects on specific targets are not fully understood. ETP, early thymic progenitor; CMP, common myeloid progenitor; cTEC, cortical thymic epithelial cell; DC, dendritic cell: ILC, innate lymphoid cell; HSC, haematopoietic stem cell; MPP, multipotent progenitor; MSC, mesenchymal stromal cell; mTEC, medullary thymic epithelial cell; RTE, recent thymic emigrant.