Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 20, Issue 1, Pages 75-87Publisher
WILEY
DOI: 10.1111/ajt.15517
Keywords
alloantibody; basic (laboratory) research; science; biomarker; costimulation; immune; immunobiology; immunosuppression; immune modulation; monitoring; T cell biology; translational research; science
Categories
Funding
- Emory University Research Committee Award
- [T32 AI070081]
- [F31 AI145178]
- [R01 AI073707]
- [K08 AI132747]
- [RO1 AI104699]
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Donor-specific antibodies (DSAs) contribute to renal allograft loss. However, biomarkers to guide clinical management of DSA posttransplant or detect humoral alloimmune responses before alloantibodies develop are not available. Circulating T follicular helper (cTfh) cells are CD4(+)CXCR5(+) Tfh-like cells in the blood that have been associated with alloantibodies in transplant recipients, but whether they precede antibody formation for their evaluation as a predictive biomarker in transplant is unknown. To evaluate the ability of cTfh cells to predict DSA, we used murine transplant models to determine the temporal relationship between cTfh cells, germinal center formation, and DSA development. We observed that donor-reactive CD4(+)CXCR5(+) cTfh cells expand after allotransplant. These cTfh cells were equivalent to graft-draining lymph node-derived Tfh cells in their ability to provide B cell help for antibody production. cTfh cell expansion and differentiation into ICOS+PD-1(+) cells temporally correlated with germinal center alloreactivity and preceded the generation of DSAs in instances of modified and unmodified alloantibody formation. Importantly, delayed costimulation blockade initiated after the detection of ICOS+PD-1(+) cTfh cells prevented DSAs. These findings suggest that cTfh cells could serve as a biomarker for humoral alloreactivity before the detection of alloantibodies and inform therapeutic approaches to prevent DSAs.
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