SUMMARY Tissue-resident memory T cells (TRM) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRM remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells comprise a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69−TEM cells in tissues and circulation, and defines human TRM based on homology to the transcriptional profile of mouse CD8+TRM. Human TRM in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced proliferation compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies.

No abstract

SUMMARY Maturation and migration to lymph nodes (LNs) constitutes a central paradigm in conventional dendritic cell (cDC) biology, but remains poorly defined in humans. Using our organ donor tissue resource, we analyzed cDC subset distribution, maturation and migration in mucosal tissues (lungs, intestines), associated lymph nodes (LNs), and other lymphoid sites from 78 individuals aged <1–93years. The distribution of cDC1 (CD141hiCD13hi) and cDC2 (Sirp-α+CD1c+) subsets was a function of tissue site and conserved between donors. We identified cDC2 as the major mature (HLA-DRhi) subset in LNs with the highest frequency in lung-draining LNs. Mature cDC2 in mucosal-draining LNs expressed tissue-specific markers derived from the paired mucosal site, reflecting their tissue-migratory origin. These distribution and maturation patterns were largely maintained throughout life, with site-specific variations. Our findings provide evidence for localized DC tissue surveillance and reveal a lifelong division of labor between DC subsets, with cDC2 functioning as guardians of the mucosa.

SUMMARYTissue-resident memory T cells (TRM) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRM remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells comprise a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69 + subset of memory CD4 + and CD8 + T cells in lung and spleen that is distinct from that of CD69 − TEM cells in tissues and circulation, and defines human TRM based on homology to the transcriptional profile of mouse CD8 + TRM. Human TRM in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced proliferation compared with circulating TEM, suggesting * Correspondence and lead contact: df2396@cumc.columbia.edu. 6 These authors contributed equally. 7 Senior author Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AUTHOR CONTRIBUTIONS ACCESSION NUMBERSThe accession number for the RNA-Seq data reported in this paper is GEO: GSE94964. HHS Public Access eTOC BlurbKumar et al. identify a core transcriptional and phenotypic signature which defines human TRM for both CD4 + and CD8 + T cells that is preserved across diverse individuals and in mucosal and lymphoid sites.

B cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B cell clones are distributed in the body, we sequenced 933,427 B cell clonal lineages and mapped them to 8 different anatomic compartments in 6 human organ donors. We show that large B cell clones partition into two broad networks—one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.