Follicular T cells mediate donor-specific antibody and rejection after solid organ transplantation

Mostafa T. Mohammed, Songjie Cai, Benjamin L. Hanson, Hengcheng Zhang, Rachel L. Clement, Joe Daccache, Cecilia B. Cavazzoni, Bruce R. Blazar, Alessandro Alessandrini, Helmut G. Rennke, Anil Chandraker, Peter T. Sage

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Following solid organ transplantation, a substantial proportion of chronic allograft loss is attributed to the formation of donor-specific antibodies (DSAs) and antibody-mediated rejection (AbMR). The frequency and phenotype of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells is altered in the setting of kidney transplantation, particularly in patients who develop AbMR. However, the roles of Tfh and Tfr cells in AbMR after solid organ transplantation is unclear. We developed mouse models to inducibly and potently perturb Tfh and Tfr cells to assess the roles of these cells in the development of DSA and AbMR. We found that Tfh cells are required for both de novo DSA responses as well as augmentation of DSA following presensitization. Using orthotopic allogeneic kidney transplantation models, we found that deletion of Tfh cells at the time of transplantation resulted in less severe transplant rejection. Furthermore, using inducible Tfr cell deletion strategies we found that Tfr cells inhibit de novo DSA formation but only have a minor role in controlling kidney transplant rejection. These studies demonstrate that Tfh cells promote, whereas Tfr cells inhibit, DSA to control rejection after kidney transplantation. Therefore, targeting these cells represent a new therapeutic strategy to prevent and treat AbMR.

Original languageEnglish (US)
Pages (from-to)1893-1901
Number of pages9
JournalAmerican Journal of Transplantation
Volume21
Issue number5
Early online dateJan 9 2021
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
The authors thank Dr. Ivy Rosales for help with immunohistochemistry. This work was supported by the National Institute of Health through grants K22AI132937 (P.T.S.), P01AI056299 (P.T.S., B.R.B.), and R3734495 (B.R.B.).

Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons

Keywords

  • B cell biology
  • alloantibody
  • animal models: murine
  • basic (laboratory) research / science
  • immune regulation
  • immunosuppression / immune modulation
  • kidney transplantation / nephrology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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