T cell regeneration after immunological injury

Abstract

Recovery of immunocompetence after periods of haematopoietic stress or injury is crucial not only for efficient responses against pathogens and tumour antigens but also for optimal responses to immunotherapy for cancer. In contrast to the early recovery of innate cells, including neutrophils, natural killer (NK) cells and monocytes, adaptive immune cells, in particular T cells, recover at a much slower pace and are particularly sensitive to negative insults caused by infections or cytoreductive chemotherapy and radiotherapy. Constrictions in the diversity of the T cell pool have been associated with impaired immune responses to several antigens 1-3 and adverse clinical outcomes in patients receiving haematopoietic cell transplantation (HCT) 4,5. The capacity of T cells to mount and maintain effective responses to a wide variety of antigens depends on a large repertoire of unique T cell receptors (TCRs) generated in the thymus during the process of T cell development. This process is dependent on crosstalk between bone marrow (BM)-derived T cell progenitors and the supportive thymic stromal microenvironment, which primarily consists of thymic epithelial cells (TECs), endothelial cells, mesenchymal stromal cells, dendritic cells and macrophages 6. Although, for example, T cell proliferation, driven by interleukin-7 (IL-7) and IL-15, in response to lymphopenic conditions can contribute to numerical reconstitution of T cells, complete long-term recovery of a diverse and functional T cell pool requires reactivation of thymic function and de novo T cell generation (Fig. 1). However, the thymus is sensitive to various injuries, such as those caused by cytoreductive treatments, infection, septic shock and graft-versus-host disease (GVHD). Furthermore,

Immune Reconstitution in the Aging Host: Opportunities for Mechanism-Based Therapy in Allogeneic Hematopoietic Cell Transplantation

“…Clinically speaking, immune reconstitution post allogeneic HCT in older patients follows similar pattern as younger patients, with both thymus-dependent and independent mechanisms (44,62). However, the aging of the immune system especially the thymus and the bone marrow significantly impact the kinetics of immune reconstitution, resulting in suboptimal clinical outcomes among older patients post allogeneic HCT.…”

“…These senescent Tcells have been associated with chronic viral infections, reduced IL-2 production, increased IL-6 production, and decreased antitumor effector activities (41,42). Delayed T-cell immune reconstitution in older adults most likely results from ageassociated thymic functional decline and the aging host environment in the bone marrow as well as other lymphoid organs (43,44). Functionally, T-cell aging and delayed immune reconstitution affects T-cell immunity and in the context of allogeneic HCT, may affect the ability to defend against various infections and disease relapse.…”

“…This is crucial in aging patients where thymic atrophy due to involution is common, resulting in impaired recovery and increased risks of infection among older patients. In contrast, CD8+ T-cells predominantly expand in the periphery thus may be less sensitive to the effect of aging (44,62). Interestingly, a recent large-scale genome-wide association study has suggested that besides age and gender, a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus is associated with increased thymopoiesis and T cell diversity in transplantation models (64).…”

“…Moreover, infection with many human herpesviruses especially cytomegalovirus (CMV) has significant impact on the pattern and repertoire of overall T cell and CMV-specific immunity post-allogeneic HCT (65,66). For further details of thymus-dependent mechanism underlying immune reconstitution and various enhancement strategies, the readers are referred to an excellent recent review (44).…”

An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation

“…Two different processes contribute to the long-term T cell pool in post-transplant patients: initially, the T cells transplanted in the graft proliferate in the blood and peripheral organs of the lymphopenic recipient, and subsequently, lymphoid precursors from the transplanted stem cells are generated in the bone marrow and undergo selection in the recipient thymus. The latter truly de novo production of T cells begins after the recovery of the thymus from conditioning induced damage, and can be influenced by the further damage that occurs if GVHD develops ( 16 ). In contrast, B cells can remain at below-normal levels for years following transplantation.…”