Preterminal host dendritic cells in irradiated mice prime CD8+ T cell–mediated acute graft-versus-host disease
Yi Zhang, … , Adam J. Rivera, Stephen G. Emerson
Yi Zhang, … , Adam J. Rivera, Stephen G. Emerson
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1335-1344. https://doi.org/10.1172/JCI14989.
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Article Immunology

Preterminal host dendritic cells in irradiated mice prime CD8+ T cell–mediated acute graft-versus-host disease

Abstract

To understand the relationship between host antigen-presenting cells (APCs) and donor T cells in initiating graft-versus-host disease (GVHD), we followed the fate of host dendritic cells (DCs) in irradiated C57BL/6 (B6) recipient mice and the interaction of these cells with minor histocompatibility antigen- (miHA-) mismatched CD8+ T cells from C3H.SW donors. Host CD11c+ DCs were rapidly activated and aggregated in the T cell areas of the spleen within 6 hours of lethal irradiation. By 5 days after irradiation, <1% of host DCs were detectable, but the activated donor CD8+ T cells had already undergone as many as seven divisions. Thus, proliferation of donor CD8+ T cells preceded the disappearance of host DCs. When C3H.SW donor CD8+ T cells were primed in vivo in irradiated B6 mice or ex vivo by host CD11c+ DCs for 24–36 hours, they were able to proliferate and differentiate into IFN-γ–producing cells in β2-microglobulin–deficient (β2m–/–) B6 recipients and to mediate acute GVHD in β2m–/– → B6 chimeric mice. These results indicate that, although host DCs disappear rapidly after allogeneic bone marrow transplantation, they prime donor T cells before their disappearance and play a critical role in triggering donor CD8+ T cell–mediated GVHD.

Authors

Yi Zhang, Jean-Pierre Louboutin, Jiang Zhu, Adam J. Rivera, Stephen G. Emerson

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Figure 1

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Development of acute GVHD in B6 recipients transplanted with C3H.SW T–BM...
Development of acute GVHD in B6 recipients transplanted with C3H.SW T–BM cells and CD8+ T cells. (a) Recipient weight loss and (b) actuarial survival rate. Recipients were conditioned with 9.5 Gy TBI and then administered 7 × 106 C3H.SW T–BM cells alone (n = 12; diamonds) or along with 3 × 106 C3H.SW CD8+ T cells (n = 17; squares). Data are derived from three separate experiments. (c) Infiltration of lymphocytes and CD8+ T cells in liver and skin (arrows) during GVHD. Livers and skin were harvested from mice and sectioned for histologic staining with hematoxylin and eosin (HE) and immunohistochemical staining with anti-CD8 Ab as described in Methods. Magnification: left, ×100; right, ×200. (d) Intracellular IFN-γ expression in hepatic CD8+ T lymphocytes. Hepatic lymphocytes were isolated from mice and restimulated in vitro in the presence or absence of anti-CD3 Ab plus MC57SV cells (H-2Db) irradiated with 30 Gy for 16 hours. Lymphocytes were then labeled with anti-CD8 and anti-CD11a Ab’s, fixed, permeabilized, and labeled with anti–IFN-γ Ab. The expression of intracellular IFN-γ in CD8+ T cells was quantitated by flow cytometry. Dot plots shown are from IFN-γ and CD11a labeling of gated CD8+ T cells.