Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome

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Science Immunology  07 Oct 2016:
Vol. 1, Issue 4, eaah3732
DOI: 10.1126/sciimmunol.aah3732

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Transplantation stalemate

Successful organ transplantation depends on both preventing rejection of the graft by host cells [host versus graft (HvG)] and blocking graft cells that attack the host (GvH). Zuber et al. demonstrated that a balance in this two-way alloreactivity affected clinical outcomes in organ transplant recipients. They examined gut-resident T cell turnover kinetics in human intestinal allografts and found that HvG-reactive cells persisted long-term in the graft, acquiring a tissue-resident phenotype. However, GvH-reactive cells expanded within the graft in the absence of rejection. The GvH-reactive cells may balance out the HvG-reactive cells, preventing rejection.


One paradigm in transplantation is that graft-infiltrating T cells are largely nonalloreactive “bystander” cells. However, the origin and specificity of allograft T cells over time have not been investigated in detail in animals or humans. We used polychromatic flow cytometry and high-throughput T cell receptor sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intragraft host-versus-graft (HvG) and graft-versus-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted in the long term in the graft. Early expansion of GvH clones in the graft correlated with the rapid replacement of donor antigen-presenting cells by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2DHi CD8+ αβ T cells, marked predominance of HvG clones, and accelerated T cell turnover in the graft. Ultimately, these recipient T cells acquired a steady-state tissue-resident phenotype but regained CD28 expression during rejections. Increased ratios of GvH to HvG clones were seen in nonrejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population.

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