Integrated B and T cell repertoire analysis reveals organized but heterogeneous adaptive immunity in chronic experimental stroke

Ischemic stroke drives prolonged accumulation of lymphocytes within the injured brain, and we recently showed that the T-cell compartment of the chronic infarct is not a random infiltrate but a reproducibly organized oligoclonal repertoire. Whether this organization is a broader property of the post-stroke adaptive immune response, extending to B cells and coordinated across lymphocyte lineages, has remained unknown. Here we performed immunoglobulin heavy-chain (IGH) repertoire sequencing of chronic infarct tissue across different cohorts spanning age, sex, experimental stroke models, and independent study centers, and integrated these data with T-cell receptor β (TRB) repertoires from the same lesions. Chronic infarcts exhibited increased B-cell receptor clonality relative to matched splenic repertoires, a pattern reproducible across age, sex, models, and centers, yet heterogeneous among individual lesions owing to variable expansion of dominant clonotypes. Dominant B-cell clonotypes showed recurrent V(D)J gene usage across animals, and a subset of recurrent receptor frameworks contained public CDR3 amino-acid sequences despite substantial overall sequence diversity. Integrated analysis revealed that B- and T-cell repertoire concentration was positively associated within individual infarcts while remaining heterogeneous in its relative organization across lesions, and complementary immunoglobulin light-chain analyses supported the overall pattern of localized B-cell remodeling. Together, these findings show that persistent adaptive immunity after stroke is organized across multiple hierarchical levels, from clonal concentration to recurrent receptor architecture and paired B- and T-cell repertoire organization, yet remains biologically heterogeneous across individuals. This organizational framework, together with the publicly deposited repertoire dataset, provides a foundation for future studies of the antigenic drivers and functional consequences of chronic post-stroke adaptive immunity.

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Journal
Journal of Neuroinflammation
Published
2026-11-04
DOI
https://doi.org/10.1186/s12974-026-04112-7
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
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article

Integrated B and T cell repertoire analysis reveals organized but heterogeneous adaptive immunity in chronic experimental stroke

Daniel Berchtold, Rick G. Schnellmann, Stuart McRae Allan, María Ángeles Moro et al.
2 links
Journal of Neuroinflammation
Neuroinflammation and Neurodegeneration Mechanisms
article

Integrated B and T cell repertoire analysis reveals organized but heterogeneous adaptive immunity in chronic experimental stroke

Daniel Berchtold, Rick G. Schnellmann, Stuart McRae Allan, María Ángeles Moro, Marion S. Buckwalter, Gaia Brezzo, Barry W. McColl, Lizi M. Hegarty, Rachel H. Crumpacker, Danielle A. Becktel, Susan A. Whitman, Josef Anrather, Claudia Dames, Jennifer E. Goertz, Helena Willington Morrison, Christian Meisel, Kristian P. Doyle, Alicia García‐Culebras, Jacob C. Zbesko, Craig J. Smith, Kristy A. Zera, Erin D. Chapman, Sangeetha Senthil Kumar, Andreas Meisel, María I. Cuartero
article en

Abstract

Ischemic stroke drives prolonged accumulation of lymphocytes within the injured brain, and we recently showed that the T-cell compartment of the chronic infarct is not a random infiltrate but a reproducibly organized oligoclonal repertoire. Whether this organization is a broader property of the post-stroke adaptive immune response, extending to B cells and coordinated across lymphocyte lineages, has remained unknown. Here we performed immunoglobulin heavy-chain (IGH) repertoire sequencing of chronic infarct tissue across different cohorts spanning age, sex, experimental stroke models, and independent study centers, and integrated these data with T-cell receptor β (TRB) repertoires from the same lesions. Chronic infarcts exhibited increased B-cell receptor clonality relative to matched splenic repertoires, a pattern reproducible across age, sex, models, and centers, yet heterogeneous among individual lesions owing to variable expansion of dominant clonotypes. Dominant B-cell clonotypes showed recurrent V(D)J gene usage across animals, and a subset of recurrent receptor frameworks contained public CDR3 amino-acid sequences despite substantial overall sequence diversity. Integrated analysis revealed that B- and T-cell repertoire concentration was positively associated within individual infarcts while remaining heterogeneous in its relative organization across lesions, and complementary immunoglobulin light-chain analyses supported the overall pattern of localized B-cell remodeling. Together, these findings show that persistent adaptive immunity after stroke is organized across multiple hierarchical levels, from clonal concentration to recurrent receptor architecture and paired B- and T-cell repertoire organization, yet remains biologically heterogeneous across individuals. This organizational framework, together with the publicly deposited repertoire dataset, provides a foundation for future studies of the antigenic drivers and functional consequences of chronic post-stroke adaptive immunity.

Journal of Neuroinflammation
University of Arizona (US), Spanish National Centre for Cardiovascular Research (ES), University of Manchester (GB), Stanford Medicine (US), Weill Cornell Medicine (US), Charité - Universitätsmedizin Berlin (DE), Stanford University (US), University of Edinburgh (GB)
U.S. Department of Veterans Affairs, Alzheimer's Association, American Heart Association, Foundation for Cardiovascular Research, Ministerio de Ciencia, Innovación y Universidades, European Commission, Deutsche Forschungsgemeinschaft, Fondation Leducq, Centro Nacional de Investigaciones Cardiovasculares, UK Dementia Research Institute, Medical Research Council, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Good health and well-being
Openalex Percentile: Top 41%
Neuroinflammation and Neurodegeneration Mechanisms
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