Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity

Abstract

Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8 + memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.

The road to purified hematopoietic stem cell transplants is paved with antibodies

“…Co-transplantation with purified HSC and T cell subpopulations with targeted anti-tumor or anti-pathogen activity may be a useful strategy for providing stem cell replacement and rapid disease-specific functional immunity to improve outcomes. As a proof-of-concept example of this approach, Müller and colleagues recently demonstrated transplantation of mice with purified allogeneic HSC plus tetramer-selected T cells directed against murine cytomegalovirus (MCMV) [49*]. Massive expansion of functional anti-MCMV specific T cells with enhanced anti-viral immunity was observed in comparison with recipients of HSC plus unselected T cells.…”

“…Massive expansion of functional anti-MCMV specific T cells with enhanced anti-viral immunity was observed in comparison with recipients of HSC plus unselected T cells. De novo T cell immunity arising from the donor HSC was also significantly improved [49*], indicating this strategy may lead to better qualitative immune recovery than with unmanipulated grafts that involve crude whole T cell adoptive transfer.…”

Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance

“…The data in (C) represent total percentage; one way ANOVA was performed, where *p % 0.05 and **p % 0.01. Data and error bars in (D), (E), and (G) represent means ± SD; one-way ANOVA was performed, where *p % 0.05, **p % 0.01, and ***p % 0.001. host, resulting in potentially lethal organ damage as well as immune deficiency caused by lymphoid organ homing donor T cells (Gallatin et al, 1986;Krensky et al, 1990;Weissman, 2000;Tsao et al, 2009;M€ uller et al, 2012a). GvHD can be avoided by transplanting purified HSCs, which lack mature T cells (Shizuru et al, 1996;Uchida et al, 1998).…”

Donor Allospecific CD44high Central Memory T Cells Have Decreased Ability to Mediate Graft-vs.-Host Disease

“…It has previously been reported that common virus specific memory T cells including EBV-specific and CMV-specific memory T cells do not GVHD in humans (7–11). However, since alloreactive memory T cells can be generated either by cross-reaction or allospecific memory reaction, it is important to further understand the biology and pathogenesis of the true allospecific memory T cells in GVHD.…”