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Modeling human adaptive immune responses with tonsil organoids.

ABSTRACT: Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.

SUBMITTER: Wagar LE

PROVIDER: S-EPMC7891554 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Modeling human adaptive immune responses with tonsil organoids.

Wagar Lisa E LE Salahudeen Ameen A Constantz Christian M CM Wendel Ben S BS Lyons Michael M MM Mallajosyula Vamsee V Jatt Lauren P LP Adamska Julia Z JZ Blum Lisa K LK Gupta Neha N Jackson Katherine J L KJL Yang Fan F Röltgen Katharina K Roskin Krishna M KM Blaine Kelly M KM Meister Kara D KD Ahmad Iram N IN Cortese Mario M Dora Emery G EG Tucker Sean N SN Sperling Anne I AI Jain Aarti A Davies D Huw DH Felgner Philip L PL Hammer Gregory B GB Kim Peter S PS Robinson William H WH Boyd Scott D SD Kuo Calvin J CJ Davis Mark M MM

Nature medicine 20210111 1

Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hy ...[more]

PMID: 33432170

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Project description:Background and aimsCrohn's disease and ulcerative colitis are characterized by dysregulated adaptive immune responses to the microbiota in genetically susceptible individuals, but the specificity of these responses remains largely undefined. Therefore, we developed a microbiota antigen microarray to characterize microbial antibody reactivity, particularly to human-derived microbiota flagellins, in inflammatory bowel disease.MethodsSera from healthy volunteers (n = 87) at the University of Alabama at Birmingham and from patients recruited from the Kirklin Clinic of University of Alabama at Birmingham Hospital, including patients with Crohn's disease (n = 152) and ulcerative colitis (n = 170), were individually probed against microbiota bacterial flagellins of both mouse and human origin and analyzed for IgG and IgA antibody responses. Circulating flagellin-reactive T effector (CD4+CD154+) and T regulatory (CD4+CD137+) cells were isolated and evaluated in selected patients. Resulting adaptive immune responses were compared with corresponding clinical data to determine relevancy to disease behavior.ResultsWe show that patients with IBD express selective patterns of antibody reactivity to microbiota flagellins. Patients with Crohn's disease, but not patients with ulcerative colitis, display augmented serum IgG to human ileal-localized Lachnospiraceae flagellins, with a subset of patients having high responses to more than 10 flagellins. Elevated responses to CBir1, a mouse Lachnospiraceae flagellin used clinically to diagnose CD, correlated with multi-Lachnospiraceae flagellin reactivity. In this subset of patients with CD, multi-flagellin reactivity was associated with elevated flagellin-specific CD154+CD45RA- T memory cells, a reduced ratio of flagellin-reactive CD4+ T regulatory to T effector cells, and a high frequency of disease complications.ConclusionsPatients with Crohn's disease display strong adaptive immune response to human-derived Lachnospiraceae flagellins, which may be targeted for prognosis and future personalized therapies.

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Modeling human adaptive immune responses with tonsil organoids.

Publications

Modeling human adaptive immune responses with tonsil organoids.

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