Bhattacharya, D., Rossi, D. J., Bryder, D. & Weissman, I. L. Purified hematopoietic stem cell engraftment of rare niches corrects severe lymphoid deficiencies without host conditioning. J. Exp. Med. 203, 73-85

Department of Pathology, Institute of Cancer and Stem Cell Biology and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 02/2006; 203(1):73-85. DOI: 10.1084/jem.20051714
Source: PubMed


In the absence of irradiation or other cytoreductive conditioning, endogenous hematopoietic stem cells (HSCs) are thought to fill the unique niches within the bone marrow that allow maintenance of full hematopoietic potential and thus prevent productive engraftment of transplanted donor HSCs. By transplantation of purified exogenous HSCs into unconditioned congenic histocompatible strains of mice, we show that approximately 0.1-1.0% of these HSC niches are available for engraftment at any given point and find no evidence that endogenous HSCs can be displaced from the niches they occupy. We demonstrate that productive engraftment of HSCs within these empty niches is inhibited by host CD4+ T cells that recognize very subtle minor histocompatibility differences. Strikingly, transplantation of purified HSCs into a panel of severe combined immunodeficient (SCID) mice leads to a rapid and complete rescue of lymphoid deficiencies through engraftment of these very rare niches and expansion of donor lymphoid progenitors. We further demonstrate that transient antibody-mediated depletion of CD4+ T cells allows short-term HSC engraftment and regeneration of B cells in a mouse model of B(-) non-SCID. These experiments provide a general mechanism by which transplanted HSCs can correct hematopoietic deficiencies without any host conditioning or with only highly specific and transient lymphoablation.

Download full-text


Available from: David Bryder
  • Source
    • ".2 + P14xTcra À/À donors (from Taconic) into congenic CD45.1 + recipients (from Jackson Labs or Taconic) to monitor long-term persistence and recall of CD45.2 + cells. However, the transferred cells disappeared within $3–4 weeks (data not shown), suggesting that differences between the P14xTcra À/À and both CD45.1 + strains (per their vendors on a C57BL/6 background) elicited a host response against cryptic alloantigens (Bhattacharya et al., 2006 "
    [Show abstract] [Hide abstract]
    ABSTRACT: T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8(+) T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics.
    Full-text · Article · Sep 2013 · Immunity
  • Source
    • "GFP-labeled B cell progenitors were retroorbitally injected into unconditioned 4 to 8-week-old Rag2 À/À /IL2Rcc À/À mice [26] "
    [Show abstract] [Hide abstract]
    ABSTRACT: The lymphoid potential of the hematopoietic system is observed as early as embryonic day 9 (E9) before transplantable hematopoietic stem cells (HSCs) appear at E11 in mice. However, it is largely unknown as to which cell fraction is responsible for the initial wave of lymphopoiesis and whether these earliest lymphocytes make any contributions to the adult lymphoid system. We previously isolated the earliest hematolymphoid progenitors at E9 that had CD45(+)c-Kit(+)AA4.1(+) phenotypes. In this study, the differentiation potency into B cell subsets of the E9 hematolymphoid progenitors was examined in detail. In culture, E9 hematolymphoid progenitors produced B220(-/low) B cell progenitors in striking contrast to adult BM c-Kit(+)Sca-1(+)Lin(-) cells. Upon in vivo transplantation, B cell progenitors derived from E9 hematolymphoid progenitors preferentially differentiated into the B-1 B lymphocyte subset, whereas their differentiation into B-2 B lymphocyte subsets [follicular B (FoB), marginal zone B (MZB) cells] was inefficient. Of note, these donor B lymphocytes permanently repopulated in host mice, even if adult mice were used as recipients. These results suggest that B cell progenitors produced from an initial wave of definitive hematopoiesis before authentic HSCs appear could be a permanent source for, at least, the B-1 B lymphocyte subset.
    Preview · Article · Jun 2013 · Biochemical and Biophysical Research Communications
  • Source
    • "Besides OVA, human c-MYC (in the double transgenic model) or human c-MYC plus GFP (in the retrovirally transduced lymphoma model) are expressed as foreign antigens whose potential as tumor rejection antigens have not been explored. The latter is particularly important as GFP is frequently introduced into tumors without accounting for its immunogenic potential [28]. When OVA, GFP, or OVA plus GFP were expressed in these cells, tumors were rejected except for a few cases in which tumor outgrowth resumed after a considerable delay. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60-70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80-100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches.
    Full-text · Article · Mar 2012 · PLoS ONE
Show more