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T cell Allorecognition Pathways in Solid Organ Transplantation
Open accessAbstract
Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells – the semi-direct pathway – suggests that the conventional view may be an oversimplification. We review recent advances in our understanding of how the different T cell allorecognition pathways are triggered, consider how this generates effector alloantibody and cytotoxic CD8 T cell alloresponses and assess how these responses contribute to early and late allograft rejection. We further discuss how this knowledge may inform development of cellular and pharmacological therapies that aim to improve transplant outcomes, with focus on the use of induced regulatory T cells with indirect allospecificity and on the development of immunometabolic strategies.
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“The direct pathway provokes the most vigorous immune response by directly representing MHC I and MHC II molecules of the donor’s APCs to recipient CD8 and CD4 T cells, respectively.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [10]
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“Activated recipient T cells migrate to the graft site, directly recognize foreign antigens, and participate in acute rejection.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [10]
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“Although this pathway invokes a less vigorous response, it lasts longer due to the available supply of host APCs and foreign antigens within the grafts.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [10]
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“This response vanishes within a few weeks because of a limited number of donor APCs and their depletion over time [10].”
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“Moreover, CD4 T cells have a substantial role in regulating both humoral and cytotoxic T cell responses as the main elements of chronic rejection.”
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“Accordingly, indirect pathway activity is crucial to graft fate [10].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [10]
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Metadata
- Authors
- Siu, J. H. Y., Surendrakumar, V., Richards, J. A., & Pettigrew, G. J.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Pettigrew, Gavin J.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2018-11-05
- Volume
- 9
- Pages
- 2548-2548
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC6230624
- OpenAlex
- W2900406950
- Cited by
- 223
- References
- 153
- Citations by year
- 2026: 9 · 2025: 29 · 2024: 34 · 2023: 48 · 2022: 34 · 2021: 42 · 2020: 25 · 2019: 2
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Apollo (cc-by)
- Funders
- National Institute for Health and Care Research (CL-2015-14-002)
- British Heart Foundation (FS/12/87/29899)
- Cambridge Trust
- Evelyn Trust
- Gates Cambridge Trust
- Mason Medical Research Trust
- NIHR Cambridge Biomedical Research Centre
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Keywords
- solid organ transplantation, dendritic cell antigen presentation, acute rejection, chronic rejection, alloantibodies, CD8+ cytotoxic T lymphocytes, regulatory T cells, allograft rejection
- MeSH terms
- Histocompatibility Antigens Class II, Dendritic Cells, Graft Rejection, T-Lymphocytes, Helper-Inducer, Humans, Isoantibodies, Isoantigens, T-Lymphocytes, Cytotoxic, Transplantation, Homologous, Organ Transplantation, T-Lymphocytes, Regulatory
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