Abstract
T cells play a critical role in mediating antigen-specific and long-term immunity against viral and bacterial pathogens, and their development relies on the highly specialized thymic microenvironment. T cell immunodeficiency can be acquired in the form of inborn errors, or can result from perturbations to the thymus due to aging or irradiation/chemotherapy required for cancer treatment. Hematopoietic stem cell transplant (HSCT) from compatible donors is a cornerstone for the treatment of hematological malignancies and immunodeficiency. Although it can restore a functional immune system, profound impairments exist in recovery of the T cell compartment. T cells remain absent or low in number for many months after HSCT, depending on a variety of factors including the age of the recipient. While younger patients have a shorter refractory period, the prolonged T cell recovery observed in older patients can lead to a higher risk of opportunistic infections and increased predisposition to relapse. Thus, strategies for enhancing T cell recovery in aged individuals are needed to counter thymic damage induced by radiation and chemotherapy toxicities, in addition to naturally occurring age-related thymic involution. Preclinical results have shown that robust and rapid long-term thymic reconstitution can be achieved when progenitor T cells, generated in vitro from HSCs, are co-administered during HSCT. Progenitor T cells appear to rely on lymphostromal crosstalk via receptor activator of NF-κB (RANK) and RANK-ligand (RANKL) interactions, creating chemokine-rich niches within the cortex and medulla that likely favor the recruitment of bone marrow-derived thymus seeding progenitors. Here, we employed preclinical mouse models to demonstrate that in vitro-generated progenitor T cells can effectively engraft involuted aged thymuses, which could potentially improve T cell recovery. The utility of progenitor T cells for aged recipients positions them as a promising cellular therapy for immune recovery and intrathymic repair following irradiation and chemotherapy, even in a post-involution thymus.
Highlights
T cells are essential mediators of antigen-specific, longterm adaptive immunity
The thymus is responsible for the development of self-tolerant, immunocompetent T cells, but given a lack of self-renewing cells, is continually reliant on replenishment of new T cell progenitors derived from bone marrow (BM) hematopoietic stem cells (HSCs)
In vitro-derived T cells exhibited early graft vs. tumor activity in hematopoietic stem cell transplantation (HSCT) recipients [95]. We extended this to humans and characterized a CD34+CD7++ proT cell subset generated from umbilical cord blood (UCB)-HSC co-cultures with OP9-DL1 cells [96]
Summary
T cells are essential mediators of antigen-specific, longterm adaptive immunity. The thymus is responsible for the development of self-tolerant, immunocompetent T cells, but given a lack of self-renewing cells, is continually reliant on replenishment of new T cell progenitors derived from bone marrow (BM) hematopoietic stem cells (HSCs). It leads to blurred definition of boundaries between the medullary and cortical regions, suggesting inadequacies in TEC function [72] In support of this notion, the age-related decrease in Aire expression in the medulla and abnormally low negative selection of emerging thymocytes, led to increased autoreactivity and inflammation [78]. These include keratinocyte growth factor (KGF) administration for protecting TECs during irradiation-induced injury [79,80,81,82], and IL-22 administration for stimulation of TEC proliferation and repair [83] These approaches have not led to rapid, early or complete restoration of the peripheral T cell compartment after transplant, and it is difficult to delineate whether these strategies directly enhance thymic activity in the aged, or, in part, due to the promotion of hematopoiesis in the BM. After proT cell adoptive transfer in preclinical mouse models, the mature functional T cells that emerge have a broad repertoire capable of combatting both cancer and infections [95, 99], and can develop into various functional subsets (effector, helper, memory) [100], while demonstrating no autoreactivity
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