title: Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome.
abstract: A paradigm in transplantation states that graft-infiltrating T cells are largely non-alloreactive "bystander" cells. However, the origin and specificity of allograft T cells over time has not been investigated in detail in animals or humans. Here, we use polychromatic flow cytometry and high throughput TCR sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intra-graft host-vs-graft (HvG) and graft-vs-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted long-term in the graft. Early expansion of GvH clones in the graft correlated with rapid replacement of donor APCs by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2DHiCD8+ alpha beta 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 non-rejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population.
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Medicine, Columbia University, New York, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Shonts
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.
authors.forename: Sai-Ping
authors.initials: SP
authors.lastname: Lau
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Obradovic
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Medicine, Columbia University, New York, USA.
authors.forename: Jianing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Medicine, Columbia University, New York, USA.
authors.forename: Suxiao
authors.initials: S
authors.lastname: Yang
authors.affiliation: INSERM UMR1149, Hôpital Robert-Debré, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Lambert
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, USA.
authors.forename: Shana
authors.initials: S
authors.lastname: Coley
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Surgery, Columbia University, New York, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Weiner
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Microbiology & Immunology, Columbia University, New York, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Thome
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Medicine, Columbia University, New York, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: DeWolf
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Surgery, Columbia University, New York, USA.|Department of Microbiology & Immunology, Columbia University, New York, USA.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
authors.affiliation: Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: INSERM UMR1149, Hôpital Robert-Debré, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Surgery, Columbia University, New York, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Griesemer
authors.affiliation: Department of Pediatrics, Columbia University, New York, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Department of Surgery, Columbia University, New York, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kato
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA.|Department of Surgery, Columbia University, New York, USA.|Department of Microbiology & Immunology, Columbia University, New York, USA.|Department of Medicine, Columbia University, New York, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes