Changes in HCMV immune cell frequency and phenotype are associated with chronic lung allograft dysfunction

Frontiers in Immunology

Immunology

Jonathan Messika¹  Martine Reynaud-Gaubert²  Aurélie Le Borgne³  Romain Kessler⁴  Antoine Roux⁵  Xavier Demant⁶  Amélie Rousselière⁷  Laurence Delbos⁷  Sophie Hombourger⁷  Béatrice Charreau⁸  Céline Bressollette-Bodin⁹  Adrien Tissot^1,10  Aurore Foureau^1,10  Loïc Falque^1,11  Jérôme Le Pavec^1,12  Véronique Boussaud^1,13  Jean-François Mornex^1,14 

[1] APHP, Nord-Université Paris Cité, Hôpital Bichat-Claude Bernard, Service de Pneumologie B et Transplantation Pulmonaire, Paris, France;Physiopathology and Epidemiology of Respiratory Diseases, UMR1152 INSERM and Université de Paris, Paris, France;CHU de Marseille, APHM, Hôpital Nord, Service de Pneumologie et Equipe de Transplantation pulmonaire; Marseille, France; Aix-Marseille Université, Marseille, France;CHU de Toulouse, Hôpital Larrey, Toulouse, France;Groupe de transplantation pulmonaire des hôpitaux universitaires de Strasbourg, Inserm-Université de Strasbourg, Strasbourg, France;Hôpital Foch, Service de pneumologie, Suresnes, France;Hôpital Haut-Lévêque, Service de pneumologie, CHU de Bordeaux, Bordeaux, France;Nantes Université, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, Nantes, France;Nantes Université, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, Nantes, France;CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, France;Nantes Université, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, Nantes, France;CHU Nantes, Nantes Université, Laboratoire de Virologie, Nantes, France;Nantes Université, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, Nantes, France;Nantes Université, CHU Nantes, Service de Pneumologie, Institut du thorax, Nantes, France;Service Hospitalier Universitaire Pneumologie et Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France;Service de Pneumologie et de Transplantation Pulmonaire, Groupe Hospitalier Marie-Lannelongue -Paris Saint Joseph, Le Plessis-Robinson, France;Université Paris-Saclay, Le Kremlin Bicêtre, France;UMR_S 999, Université Paris–Sud, Inserm, Groupe hospitalier Marie-Lannelongue-Saint Joseph, Le Plessis-Robinson, France;Service de Pneumologie, Hôpital Européen Georges-Pompidou, Paris, France;Université de Lyon, Université Lyon1, INRAE, IVPC, Lyon, France;Hospices Civils de Lyon, GHE, Service de Pneumologie, Inserm, Lyon, France;

关键词: transplantation;    CMV;    HCMV infection;    chronic lung allograft dysfunction;    CD8 T cells;    HLA-E;    UL40;    HCMV immunity;   

DOI  :  10.3389/fimmu.2023.1143875

 received in 2023-01-13, accepted in 2023-04-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundHuman cytomegalovirus (HCMV) infection is common and often severe in lung transplant recipients (LTRs), and it is a risk factor associated with chronic lung allograft dysfunction (CLAD). The complex interplay between HCMV and allograft rejection is still unclear. Currently, no treatment is available to reverse CLAD after diagnosis, and the identification of reliable biomarkers that can predict the early development of CLAD is needed. This study investigated the HCMV immunity in LTRs who will develop CLAD.MethodsThis study quantified and phenotyped conventional (HLA-A2pp65) and HLA-E-restricted (HLA-EUL40) anti-HCMV CD8+ T (CD8 T) cell responses induced by infection in LTRs developing CLAD or maintaining a stable allograft. The homeostasis of immune subsets (B, CD4T, CD8 T, NK, and γδT cells) post-primary infection associated with CLAD was also investigated.ResultsAt M18 post-transplantation, HLA-EUL40 CD8 T responses were less frequently found in HCMV+ LTRs (21.7%) developing CLAD (CLAD) than in LTRs (55%) keeping a functional graft (STABLE). In contrast, HLA-A2pp65 CD8 T was equally detected in 45% of STABLE and 47.8% of CLAD LTRs. The frequency of HLA-EUL40 and HLA-A2pp65 CD8 T among blood CD8 T cells shows lower median values in CLAD LTRs. Immunophenotype reveals an altered expression profile for HLA-EUL40 CD8 T in CLAD patients with a decreased expression for CD56 and the acquisition of PD-1. In STABLE LTRs, HCMV primary infection causes a decrease in B cells and inflation of CD8 T, CD57+/NKG2C+ NK, and δ2−γδT cells. In CLAD LTRs, the regulation of B, total CD8 T, and δ2+γδT cells is maintained, but total NK, CD57+/NKG2C+ NK, and δ2−γδT subsets are markedly reduced, while CD57 is overexpressed across T lymphocytes.ConclusionsCLAD is associated with significant changes in anti-HCMV immune cell responses. Our findings propose that the presence of dysfunctional HCMV-specific HLA-E-restricted CD8 T cells together with post-infection changes in the immune cell distribution affecting NK and γδT cells defines an early immune signature for CLAD in HCMV+ LTRs. Such a signature may be of interest for the monitoring of LTRs and may allow an early stratification of LTRs at risk of CLAD.

【 授权许可】

Unknown   
Copyright © 2023 Rousselière, Delbos, Foureau, Reynaud-Gaubert, Roux, Demant, Le Pavec, Kessler, Mornex, Messika, Falque, Le Borgne, Boussaud, Tissot, Hombourger, Bressollette-Bodin and Charreau