No abstract

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

Mucosal associated invariant T (MAIT) cells recognise conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defence, yet their functions in protection against clinically important pathogens are unknown. Here we show that mouse Legionella longbeachae infection induces MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in immunocompetent host animals. MAIT cell protection is more evident in mice lacking CD4+ cells, and adoptive transfer of MAIT cells rescues immunodeficient Rag2−/−γC−/− mice from lethal Legionella infection. Protection is dependent on MR1, IFN-γ and GM-CSF, but not IL-17A, TNF or perforin, and enhanced protection is detected earlier after infection of mice antigen-primed to boost MAIT cell numbers before infection. Our findings define a function for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.

Influenza A, B and C viruses (IAV, IBV, ICV) circulate globally and infect humans, with IAV/IBV causing most severe disease. While CD8 + T-cells confer cross-protection against different IAV strains, CD8 + T-cell responses to IBV/ICV are understudied. We dissected the CD8 + T-cell cross-reactome against influenza viruses and provided the first evidence of CD8 + T-cell cross-reactivity across IAV, IBV and ICV. Using immunopeptidomics, we identified immunodominant CD8 + T-cell epitopes from IBV, protective in mice, and found prominent memory CD8 + T-cells towards both universal and influenza type-specific epitopes in blood and lungs of healthy humans, with lung-derived CD8 + T-cells displaying a tissue-resident phenotype. Importantly, effector CD38 + Ki67 + CD8 + T-cells against novel epitopes were readily detected in IAV-and IBV-infected pediatric and adult patients. Our study introduces a new paradigm, whereby CD8 + T-cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for designing universal vaccines.

Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (T) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood. We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults. Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5CXCR3 antibody-secreting B cell population, CD21CD27 memory B cells, and CD21CD27 B cells. Activation of circulating T cells correlated with the development of both CD21 and CD21 memory B cells. However, preexisting antibodies could limit increases in serum antibody titers. IIV had no marked effect on CD8, mucosal-associated invariant T, γδ T, and natural killer cell activation. In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination. We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21CD27) B cells primarily reside within secondary lymphoid tissues and the lungs. Our study suggests that a rational design of universal vaccines needs to consider circulating T cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.