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Relative frequencies of alloantigen-specific helper CD4 T cells and B cells determine mode of antibody-mediated allograft rejection

Alsughayyir, .; Chhabra, .; Qureshi, .; Mallik, .; Ali, .; Gamper, .; Moseley, .; ... Pettigrew, GJ; + view all (2019) Relative frequencies of alloantigen-specific helper CD4 T cells and B cells determine mode of antibody-mediated allograft rejection. Frontiers in Immunology , 9 , Article 3039. 10.3389/fimmu.2018.03039. Green open access

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Abstract

Humoral alloimmunity is now recognised as a major determinant of transplant outcome. 3 MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell 4 alloresponse that underpins alloantibody generation remains poorly understood. Here, we 5 examine how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells 6 influence the humoral alloimmune response and how this relates to antibody-mediated 7 rejection (AMR). 8 An MHC-mismatched murine model of cardiac AMR was developed, in which T cell help for alloantibody responses in T cell deficient (Tcrbd−/−) C57BL/6 recipients against donor H-2Kd 9 10 MHC class I alloantigen was provided by adoptively transferred ‘TCR75’ CD4 T cells that recognise processed H-2Kd 11 allopeptide via the indirect-pathway. Transfer of large numbers (5 x 105 12 ) of TCR75 CD4 T cells was associated with rapid development of robust class-switched anti-H-2Kd 13 humoral alloimmunity and BALB/c heart grafts were rejected promptly (MST 9 days). Grafts were not rejected in T and B cell deficient Rag2-/- 14 recipients that were reconstituted with TCR75 CD4 T cells or in control (non-reconstituted) Tcrbd−/− 15 recipients, 16 suggesting that the transferred TCR75 CD4 T cells were mediating graft rejection principally 17 by providing help for effector alloantibody responses. In support, acutely rejecting BALB/c 18 heart grafts exhibited hallmark features of acute AMR, with widespread complement C4d 19 deposition, whereas cellular rejection was not evident. In addition, passive transfer of immune serum from rejecting mice to Rag2−/− 20 recipients resulted in eventual BALB/c heart 21 allograft rejection (MST 20 days). 22 Despite being long-lived, the alloantibody responses observed at rejection of the BALB/c 23 heart grafts were predominantly generated by extrafollicular foci: splenic germinal centre 24 (GC) activity had not yet developed; IgG secreting cells were confined to the splenic red pulp 25 and bridging channels; and, most convincingly, rapid graft rejection still occurred when recipients were reconstituted with similar numbers of Sh2d1a−/− 26 TCR75 CD4 T cells that are 27 genetically incapable of providing T follicular helper cell function for generating GC alloimmunity. Similarly, alloantibody responses generated in Tcrbd−/− 28 recipients reconstituted with smaller number of wild-type TCR75 CD4 T cells (103 29 ), although long30 lasting, did not have a discernible extrafollicular component, and grafts were rejected much 31 more slowly (MST 50 days). By modelling antibody responses to Hen Egg Lysozyme 32 protein, we confirm that a high ratio of antigen-specific helper T cells to B cells favours 33 development of the extrafollicular response, whereas GC activity is favoured by a relatively 34 high ratio of B cells. 35 In summary, a relative abundance of helper CD4 T cells favours development of strong 36 extrafollicular alloantibody responses that mediate acute humoral rejection, without 37 requirement for GC activity.

Type: Article
Title: Relative frequencies of alloantigen-specific helper CD4 T cells and B cells determine mode of antibody-mediated allograft rejection
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2018.03039
Publisher version: https://doi.org/10.3389/fimmu.2018.03039
Language: English
Additional information: Copyright © 2019 Alsughayyir, Chhabra, Qureshi, Mallik, Ali, Gamper, Moseley, Peacock, Kosmoliaptsis, Goddard, Linterman, Motallebzadeh and Pettigrew. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Allograft, Humoral allograft rejection, Germinal Centre (GC), Extrafollicular B cell response, Transplantation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10065803
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