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In vivo dynamics of T cells and their interactions with dendritic cells in mouse cutaneous graft-versus-host disease

Sarah Morin-Zorman, Christian Wysocki, Jieqing Zhu, Hongmei Li, Sylvain Zorman, Catherine Matte-Martone, Edwina Kisanga, Jennifer McNiff, Dhanpat Jain, David Gonzalez, David M. Rothstein, Fadi G. Lakkis, Ann Haberman and Warren D. Shlomchik

Key Points

  • Cutaneous GVHD lesions are stable, suggesting they are maintained locally.

  • Donor CD8 cells make cognate interactions with CD11c+ cells in the skin, including those that do not express Langerin.

Abstract

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloSCT). By static microscopy, cutaneous GVHD lesions contain a mix of T cells and myeloid cells. We used 2-photon intravital microscopy to investigate the dynamics of CD4+ and CD8+ T cells and donor dendritic cells (DCs) in cutaneous GVHD lesions in an MHC-matched, multiple minor histocompatibility antigen-mismatched (miHA) model. The majority of CD4 and CD8 cells were stationary, and few cells entered and stopped or were stopped and left the imaged volumes. CD8 cells made TCR:MHCI-dependent interactions with CD11c+ cells, as measured by the durations that CD8 cells contacted MHCI+ vs MHCI DCs. The acute deletion of Langerin+CD103+ DCs, which were relatively rare, did not affect CD8 cell motility and DC contact times, indicating that LangerinCD103 DCs provide stop signals to CD8 cells. CD4 cells, in contrast, had similar contact durations with MHCII+ and MHCII DCs. However, CD4 motility rapidly increased after the infusion of an MHCII-blocking antibody, indicating that TCR signaling actively suppressed CD4 movements. Many CD4 cells still were stationary after anti-MHCII antibody infusion, suggesting CD4 cell heterogeneity within the lesion. These data support a model of local GVHD maintenance within target tissues.

  • Submitted February 16, 2019.
  • Accepted May 15, 2019.
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