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Cited by 223T-cell and B-cell ImmunologyTransplantation: Methods and OutcomesRenal Transplantation Outcomes and Treatments

The DOI matches its Crossref record; 153 of the 154 references it cites were found in a registry or an index, and 1 are not checked yet.

T cell Allorecognition Pathways in Solid Organ Transplantation

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Siu, Jacqueline H. Y., Surendrakumar, Veena, Richards, James A., Pettigrew, Gavin J.·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.02548PMC PMC6230624
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Abstract

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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Crossref · 10.3389/fimmu.2018.02548

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Figures

Figure 1 Pathways of T cell allorecognition. (A) In direct pathway allorecognition, MHC Class II and Class I alloantigen is recognised as intact protein on the surface of donor antigen presenting cells (APC) by CD4 and CD8 T cells respectively. (B) In indirect allorecognition, graft alloantigen (typically MHC antigen) is internalised by recipient APC [typically a dendritic cell (DC)], processed and presented as peptide fragments in the context of recipient MHC, for self-restricted recognition by recipient T cells. Although in theory both CD4 and CD8 T cells can recognise processed alloantigen via the indirect pathway, indirect pathway CD8 T cell responses are not considered relevant for the rejection of vascularized allografts. (C) In semi-direct allorecognition, MHC alloantigen is acquired by recipient DC but, rather than presentation as processed allopeptide, is re-presented as conformationally intact protein.
Figure 1 Pathways of T cell allorecognition. (A) In direct pathway allorecognition, MHC Class II and Class I alloantigen is recognised as intact protein on the surface of donor antigen presenting cells (APC) by CD4 and CD8 T cells respectively. (B) In indirect allorecognition, graft alloantigen (typically MHC antigen) is internalised by recipient APC [typically a dendritic cell (DC)], processed and presented as peptide fragments in the context of recipient MHC, for self-restricted recognition by recipient T cells. Although in theory both CD4 and CD8 T cells can recognise processed alloantigen via the indirect pathway, indirect pathway CD8 T cell responses are not considered relevant for the rejection of vascularized allografts. (C) In semi-direct allorecognition, MHC alloantigen is acquired by recipient DC but, rather than presentation as processed allopeptide, is re-presented as conformationally intact protein.CC BY · PubMed Central
Figure 2 Delivery of CD4 T cell help for cytotoxic CD8 T cell alloimmunity. (A) For CD8 T cell responses against conventional protein antigen (such as viral antigen) following internalisation by the dendritic cell (DC), processed viral peptide is presented in the context of MHC class II and class I for CD4 and CD8 T cell recognition, respectively. CD4 T cell help is delivered to the DC, resulting in upregulation of co-stimulatory signals on the DC surface. This in turn results in enhanced presentation and more effective priming of the CD8 T cell response. (B) In transplantation, a similar three cell cluster model is achieved by donor DC presentation of intact MHC class II and class I to direct pathway CD4 and CD8 T cells. (C) Although animal models have shown that indirect pathway CD4 T cells can provide effective help for cytotoxic CD8 T cell alloresponses against intact MHC class I alloantigen, this theoretically involves a cumbersome four cell cluster with two unpaired couplets: recipient APC presenting to recipient indirect pathway CD4 T cell and donor DC presenting MHC class I alloantigen to direct pathway CD8 T cells; raising concerns regarding uncontrolled CD8 T cell alloresponses from bystander CD4 T cell activation. (D) These concerns are obviated if a recipient DC is able to re-present intact MHC class I alloantigen and processed MHC class I allopeptide simultaneously, enabling the provision of linked help from indirect pathway CD4 T cells to direct pathway CD8 T cells.
Figure 2 Delivery of CD4 T cell help for cytotoxic CD8 T cell alloimmunity. (A) For CD8 T cell responses against conventional protein antigen (such as viral antigen) following internalisation by the dendritic cell (DC), processed viral peptide is presented in the context of MHC class II and class I for CD4 and CD8 T cell recognition, respectively. CD4 T cell help is delivered to the DC, resulting in upregulation of co-stimulatory signals on the DC surface. This in turn results in enhanced presentation and more effective priming of the CD8 T cell response. (B) In transplantation, a similar three cell cluster model is achieved by donor DC presentation of intact MHC class II and class I to direct pathway CD4 and CD8 T cells. (C) Although animal models have shown that indirect pathway CD4 T cells can provide effective help for cytotoxic CD8 T cell alloresponses against intact MHC class I alloantigen, this theoretically involves a cumbersome four cell cluster with two unpaired couplets: recipient APC presenting to recipient indirect pathway CD4 T cell and donor DC presenting MHC class I alloantigen to direct pathway CD8 T cells; raising concerns regarding uncontrolled CD8 T cell alloresponses from bystander CD4 T cell activation. (D) These concerns are obviated if a recipient DC is able to re-present intact MHC class I alloantigen and processed MHC class I allopeptide simultaneously, enabling the provision of linked help from indirect pathway CD4 T cells to direct pathway CD8 T cells.CC BY · PubMed Central
Figure 3 Metabolic pathways of T cells. (A) Important metabolic pathways in T cells include glycolysis, the tricarboxylic acid (TCA) cycle (green), fatty acid oxidation (FAO), fatty acid synthesis (FAS), oxidative phosphorylation (OXPHOS) and glutaminolysis. The stars indicate reactions that generate reducing equivalents (i.e. NADH) to drive OXPHOS. Utilization of different metabolic pathways by different cell types is indicated. Greyed out pathways represent pathways that have not been defined. (B) Key metabolic pathways and inhibitors during late chronic responses are highlighted pathways by different cell types is indicated.
Figure 3 Metabolic pathways of T cells. (A) Important metabolic pathways in T cells include glycolysis, the tricarboxylic acid (TCA) cycle (green), fatty acid oxidation (FAO), fatty acid synthesis (FAS), oxidative phosphorylation (OXPHOS) and glutaminolysis. The stars indicate reactions that generate reducing equivalents (i.e. NADH) to drive OXPHOS. Utilization of different metabolic pathways by different cell types is indicated. Greyed out pathways represent pathways that have not been defined. (B) Key metabolic pathways and inhibitors during late chronic responses are highlighted pathways by different cell types is indicated.CC BY · PubMed Central

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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.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-11-05
Volume
9
Pages
2548-2548
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.02548
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
Licence
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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