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The upper airway is an important site of infection, but immune memory in the human upper airway is poorly understood, with implications for COVID-19 and many other human diseases1–4. Here we demonstrate that nasal and nasopharyngeal swabs can be used to obtain insights into these challenging problems, and define distinct immune cell populations, including antigen-specific memory B cells and T cells, in two adjacent anatomical sites in the upper airway. Upper airway immune cell populations seemed stable over time in healthy adults undergoing monthly swabs for more than 1 year, and prominent tissue resident memory T (TRM) cell and B (BRM) cell populations were defined. Unexpectedly, germinal centre cells were identified consistently in many nasopharyngeal swabs. In subjects with SARS-CoV-2 breakthrough infections, local virus-specific BRM cells, plasma cells and germinal centre B cells were identified, with evidence of local priming and an enrichment of IgA+ memory B cells in upper airway compartments compared with blood. Local plasma cell populations were identified with transcriptional profiles of longevity. Local virus-specific memory CD4+ TRM cells and CD8+ TRM cells were identified, with diverse additional virus-specific T cells. Age-dependent upper airway immunological shifts were observed. These findings provide new understanding of immune memory at a principal mucosal barrier tissue in humans.This study of immunological memory diversity in the human upper airway provides new understanding of immune memory at a major mucosal barrier tissue in humans. [ABSTRACT FROM AUTHOR]

Author(s): J. Justin Milner; Clara Toma; Bingfei Yu; Kai Zhang; Kyla Omilusik; Anthony T. Phan; Dapeng Wang; Adam J. Getzler; Toan Nguyen; Shane Crotty; Wei Wang; Matthew E. Pipkin; Ananda [...]

Author(s): Shane Crotty [1]; Ellen N. Kersh [1]; Jennifer Cannons [2]; Pamela L. Schwartzberg [2]; Rafi Ahmed (corresponding author) [1] Long-lived plasma cells and memory B cells are the primary [...]

Research designed to establish whether non-haematopoietic cells can act as antigen-presenting cells (APCs) to initiate cytotoxic T lymphocyte (CTL) responses to viruses has involved constructing bone-marrow chimaeras by lethally irradiating C57Bl/6 mice and reconstituting them with bone marrow from TAP0/0 mice. It was not possible to specifically determine the identity of the bone-marrow-derived APCs responsible for prompting CTL responses through the exogenous pathway, but it seems that macrophages and/or dendritic cells are likely to be responsible. It is clear that the exogenous pathway plays a significant role in the immune surveillance of non-haematopoietic tissues.

Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/nature24993 [ABSTRACT FROM AUTHOR]

Tissue-resident memory CD8 + T (T RM ) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses. However, the molecular signals that control T RM cell differentiation and homeostasis are not fully understood. Here we show that mouse T RM precursor cells represent a unique CD8 + T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of T RM cell differentiation and homeostasis. Runx3 was required to establish T RM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with T RM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8 + tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8 + T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of T RM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.