Host-reactive CD8+ memory stem cells in graft-versus-host disease

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Abstract

Graft-versus-host disease (GVHD) is caused by alloreactive donor T cells that trigger host tissue injury. GVHD develops over weeks or months, but how this immune response is maintained over time is unknown. In mouse models of human GVHD, we identify a new subset of postmitotic CD44loCD62LhiCD8+ T cells that generate and sustain all allogeneic T-cell subsets in GVHD reactions, including central memory, effector memory and effector CD8+ T cells, while self-renewing. These cells express Sca-1, CD122 and Bcl-2, and induce GVHD upon transfer into secondary recipients. The postmitotic CD44loCD62LhiCD8+ T cells persist throughout the course of GVHD, are generated in the initial phase in response to alloantigens and dendritic cells and require interleukin-15. Thus, their long life, ability to self-renew and multipotentiality define these cells as candidate memory stem cells. Memory stem cells will be important targets for understanding and influencing diverse chronic immune reactions, including GVHD.

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Figure 1: Identification of postmitotic CD44loCD62LhiCD8+ T cells.
Figure 2: CD44loCD62LhiCD8+ memory stem T cells induce GVH responses.
Figure 3: Host minor H antigen H60-driven development of postmitotic CD44loCD62LhiCD8+ T cells.
Figure 4: Characterization of postmitotic CD44loCD62LhiCD8+ T cells.
Figure 5: Postmitotic CD44loCD62Lhi CD8+ T cells develop during the initial phase of GVH reactions.
Figure 6: Development of postmitotic CD44loCD62LhiCD8+ T cells depends on both DCs and IL-15.

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Acknowledgements

We appreciate the pathology support given by D. Frank (Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine). This work is supported by a grant from the Specialized Center for Research from the Leukemia and Lymphoma Society of America and by grant RO1 CA102464-01 from US National Institutes of Health.

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Correspondence to Stephen G Emerson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Transplantation of B6/SJL mice with C3H.SW CD44loCD8+ T cells together with B6/SJL TCDBM induces acute GVHD, and generates donor day 42 CD44loCD62LhiCD8+ T cells. (PDF 252 kb)

Supplementary Fig. 2

Mature DCs stimulate the survival of CD8+ T cells. (PDF 54 kb)

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Zhang, Y., Joe, G., Hexner, E. et al. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med 11, 1299–1305 (2005) doi:10.1038/nm1326

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