Harnessing rejection-associated CD4 T cell epitopes for immune tolerance in transplantation Restricted; Files Only
Zhanzak, Zhuldyz (Summer 2025)
Abstract
Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSA) posing the highest rejection risk. Here, we investigated the role of indirect CD4 T cell epitopes—donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II—in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides. Antigen mapping of indirect CD4 T cell epitopes in a mouse model of fully MHC mismatched skin graft transplantation (BALB/c to C57BL/6) identified a similar epitope (amino acids 287-301) derived from the donor H2-Kd. Tetramer-binding Kd287 CD4 T cells were detected during rejection and their transfer into T cell-deficient mice induced DSA. Systemic delivery of high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287 CD4 T cells and DSA formation. Thus, targeting a narrow range of donor antigens may prevent DSA formation and improve transplant outcomes.
Table of Contents
Chapter 1. Introduction-1
1.1. Introduction-2
1.2. MHC class I immunopeptidome and direct allorecognition-4
1.3. MHC class II immunopeptidome and indirect allorecognition-7
1.4. Immunopeptidome-based biomarkers in transplantation-9
1.5. Immunopeptidome-based immunotherapy in transplantation-12
1.6. Concluding remarks-14
1.7. Figures-15
Chapter 2. Identification of rejection-associated CD4 T cell epitopes provides a target for donor-specific tolerance induction-17
2.1. Introduction-18
2.2. Methods-19
2.3. Results-27
2.3.1. The abundance of predicted indirect CD4 T cell epitopes associate with rejection and DSA development in kidney transplant patients-27
2.3.2. Epitope mapping of indirect CD4 T cells reveals polymorphic hotspots in the donor HLA-DQ protein-28
2.3.3. Epitope mapping of indirect CD4 T cells reveals polymorphic hotspots in the donor HLA-DQ protein-31
2.3.4. Kd287 is an indirect CD4 T cell epitope-32
2.3.5. Indirect polyclonal Kd287 CD4 T cells mediate the H2-Kd DSA formation-34
2.3.6. High-prevalence of public rejection-associated Kd287-specific TCRs-35
2.3.7. Systemic administration of high-dose donor H2-Kd peptides with CTLA4-Ig skews the distribution of indirect Kd287 CD4 T cells by pruning the TCR repertoire-37
2.4. Discussion-39
2.5. Limitations of the study-42
2.6. Figures-43
2.7. Supplemental Information-56
Chapter 3. Identification of rejection-associated CD4 T cell epitopes in healthy individuals-67
3.1. Introduction-68
3.2. Methods-70
3.3. Results-72
3.3.1.HLA-DQ monomer-driven expansion enhances the detection of HLA-DQ-specific CD4 T cells-72
3.3.2. Enrichment with HLA-DQ monomers clonally expands HLA-DQ-reactive CD4 T cell clones with restricted TCRab usage-74
3.3.3. Tracking HLA-DQ-specific CD4 T cell clonotypes within the naive TCR repertoire-75
3.4. Discussion-76
3.5. Limitations of the study-79
3.5. Figures-80
Chapter 4. Discussion-86
4.1. Current challenges in transplantation-87
4.2. Summary of the main findings-88
4.3. Interpretation of the main findings-90
4.4. Limitations of the study-92
4.5. Future directions-94
References-97
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File download under embargo until 21 February 2026 | 2025-06-03 11:26:18 -0400 | File download under embargo until 21 February 2026 |
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