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Lymph nodes (LNs) play critical roles in adaptive immunity by concentrating in one location the antigens, antigen-presenting cells, and antigen-responsive lymphocytes involved in such responses. Recent studies have revealed nonrandom localization of innate and adaptive immune cells within these organs, suggesting that microanatomical positioning optimizes responses involving sparse cooperating cells. Here, we report that the peripheral localization of LN cDC2 dendritic cells specialized for MHC-II antigen presentation is matched by a similarly biased paracortical distribution of CD4+ T cells directed by the chemoattractant receptor Ebi2. In the absence of Ebi2, CD4+ T cells lose their location bias and are delayed in antigen recognition, proliferative expansion, differentiation, direct effector activity, and provision of help for CD8+ T cell-mediated memory responses, limiting host defense and vaccine responses. These findings demonstrate evolutionary selection for distinct niches within the LN that promote cellular responses, emphasizing the critical link between fine-grained tissue organization and host defense. • Naive CD4+ T cells accumulate at the periphery of the T cell zone near cDC2s • CD4+ T cell-intrinsic Ebi2 expression drives intranodal peripheralization • Intranodal peripheralization ensures a temporal advantage in antigen recognition • Intranodal peripheralization is required for effective cellular immunity Host protection requires timely recognition of antigen by rare antigen-specific lymphocytes. Baptista and colleagues reveal that efficient antigen recognition by naive CD4+ T cells requires intrinsic Ebi2-mediated sensing of oxysterol gradients by promoting the preferential accumulation of these lymphocytes at the periphery of the lymph node paracortical area near cDC2s. [ABSTRACT FROM AUTHOR]

To gain insight into how an adjuvant impacts vaccination responses, we use systems immunology to study human H5N1 influenza vaccination with or without the adjuvant AS03, longitudinally assessing 14 time points including multiple time points within the first day after prime and boost. We develop an unsupervised computational framework to discover high-dimensional response patterns, which uncover adjuvant- and immunogenicity-associated early response dynamics, including some that differ post prime versus boost. With or without adjuvant, some vaccine-induced transcriptional patterns persist to at least 100 days after initial vaccination. Single-cell profiling of surface proteins, transcriptomes, and chromatin accessibility implicates transcription factors in the erythroblast-transformation-specific (ETS) family as shaping these long-lasting signatures, primarily in classical monocytes but also in CD8 + naive-like T cells. These cell-type-specific signatures are elevated at baseline in high-antibody responders in an independent vaccination cohort, suggesting that antigen-agnostic baseline immune states can be modulated by vaccine antigens alone to enhance future responses., Competing Interests: Declaration of interests R.G.v.d.M. is a former employee of and holds shares in the GSK group of companies. B.S. is a former SomaLogic, Inc. (Boulder, CO, USA), employee and a company shareholder. J.S.T. serves on the scientific advisory boards of CytoReason, Immunoscape, and the Human Immunome Project., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)