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EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335191


ABSTRACT Clinical diagnoses rely on a wide variety of laboratory tests and imaging studies, interpreted alongside physical examination and documentation of symptoms and patient history. However, the tools of diagnosis make little use of the immune system’s internal record of specific disease exposures encoded by the antigen-specific receptors of memory B cells and T cells. We have combined extensive receptor sequence datasets with three different machine learning representations of the contents of immune repertoires to develop an interpretive framework, MAchine Learning for Immunological Diagnosis (Mal-ID) , that screens for multiple illnesses simultaneously. This approach can already reliably distinguish a wide range of disease states, including specific acute or chronic infections, and autoimmune or immunodeficiency disorders, and could contribute to identifying new infectious diseases as they emerge. Importantly, many features of the model of immune receptor sequences are human-interpretable. They independently recapitulate known biology of the responses to infection by SARS-CoV-2 or HIV, and reveal common features of autoreactive immune receptor repertoires, indicating that machine learning on immune repertoires can yield new immunological knowledge.

Science ; 376(6590): eabi9591, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1731250


In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

Autoimmune Diseases , COVID-19 , Animals , CD8-Positive T-Lymphocytes , Humans , Mice , Receptors, KIR , T-Lymphocytes, Regulatory
Cell ; 185(6): 1025-1040.e14, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1649487


During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.

Antibodies, Viral , BNT162 Vaccine , COVID-19 , Germinal Center , Antigens, Viral , COVID-19/prevention & control , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Vaccination