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| Status |
Public on Sep 17, 2024 |
| Title |
Identification of rejection-associated indirect CD4 T cell epitopes provides a target for donor-specific transplant tolerance |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Other
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| Summary |
Antibody-mediated rejection, caused by antibodies against the donor human leukocyte antigen (HLA) molecules plays a fundamental role in graft rejection in transplantation. Most significant is transplant patients who generate antibodies against the donor HLA-DQ have the highest risk of rejection. In this study, we investigated the role of indirect CD4 T cell epitopes in the formation of donor-specific antibodies (DSA). Using antigen mapping techniques in kidney and heart transplant recipients with HLA-DQ DSA, we identified two polymorphic hotspots in the HLA-DQ gene that generated alloreactive CD4 T cell responses. To study the functional significance of indirect CD4 T cells, we first mapped epitopes recognised by H2-Kb C57Bl6 mice against a skin graft from H2-Kd Balb/c mice. We identified a CD4 T cell epitope, specific for amino acids 287-301 derived from the H2-Kd protein, that generated tetramer-binding Kd287+ CD4 T cells during rejection. Importantly, the transfer of Kd287+ CD4 T cells into T cell-deficient mice was sufficient to drive an antibody response against the donor H2-Kd molecule. Lastly, we found that administration of systemic high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the formation of Kd287+ CD4 T cells and diminished DSA formation. Together, these findings demonstrate that the identification of donor antigens indicates the potential for inducing donor-specific immune tolerance in transplantation.
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| Overall design |
To investigate the TCR composition and diversity of alloreactive indirect CD4 T cells, we performed TCR sequencing on flow-sorted Kd287+ CD4 T cells isolated on day 14 after transplantation in mice that exhibited donor allograft rejection and underwent peptide treatment.
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| Contributor(s) |
Larsen CP, Kissick HT, Zhanzak Z |
| Citation missing |
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| |
| Submission date |
Sep 12, 2024 |
| Last update date |
Sep 17, 2024 |
| Contact name |
Christian Larsen |
| E-mail(s) |
clarsen@emory.edu
|
| Organization name |
Emory University
|
| Department |
Department of Surgery
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| Lab |
Larsen Lab
|
| Street address |
101 Woodruff Circle
|
| City |
Atlanta |
| State/province |
Georgia |
| ZIP/Postal code |
30328 |
| Country |
USA |
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| Platforms (3) |
| GPL16417 |
Illumina MiSeq (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA1160323 |
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