Resident memory T cell development is gradual and shows AP-1 gene expression in mature cells
Neal P. Smith, Yu Yan, Youdong Pan, Jason B. Williams, Kasidet Manakongtreecheep, Shishir M. Pant, Jingxia Zhao, Tian Tian, Timothy Pan, Claire Stingley, Kevin Wu, Jiang Zhang, Alexander L. Kley, Peter K. Sorger, Alexandra-Chloé Villani, Thomas S. Kupper
Neal P. Smith, Yu Yan, Youdong Pan, Jason B. Williams, Kasidet Manakongtreecheep, Shishir M. Pant, Jingxia Zhao, Tian Tian, Timothy Pan, Claire Stingley, Kevin Wu, Jiang Zhang, Alexander L. Kley, Peter K. Sorger, Alexandra-Chloé Villani, Thomas S. Kupper
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Research Article Immunology Inflammation

Resident memory T cell development is gradual and shows AP-1 gene expression in mature cells

Abstract

Tissue-resident memory T (TRM) cells play a central role in immune responses across all barrier tissues after infection. However, the mechanisms that drive TRM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged newly generated and publicly available single-cell RNA-seq data generated across 10 developmental time points to define features of CD8+ TRM across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture gene programs that increase their expression levels in T cells transitioning from an effector to a memory state. In addition to capturing tissue-specific gene programs, we defined a temporal TRM signature across skin and siIEL that can distinguish TRM from circulating T cell populations. This TRM signature highlights biology that is missed in published signatures that compared bulk TRM to naive or nontissue resident memory populations. This temporal TRM signature included the AP-1 transcription factor family members Fos, Fosb, Fosl2, and Junb. ATAC-seq analysis detected AP-1–specific motifs at open chromatin sites in mature TRM. Cyclic immunofluorescence (CyCIF) tissue imaging detected nuclear colocalization of AP-1 members in resting CD8+ TRM greater than 100 days after infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRM biology.

Authors

Neal P. Smith, Yu Yan, Youdong Pan, Jason B. Williams, Kasidet Manakongtreecheep, Shishir M. Pant, Jingxia Zhao, Tian Tian, Timothy Pan, Claire Stingley, Kevin Wu, Jiang Zhang, Alexander L. Kley, Peter K. Sorger, Alexandra-Chloé Villani, Thomas S. Kupper

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Figure 4

Temporal TRM gene signature distinguishes TRM in mouse and human models.

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Temporal TRM gene signature distinguishes TRM in mouse and human models....
(A) UpSet plot showing the overlap between our temporal TRM signature and two previously published signatures by Milner et al. (6) and Mackay et al. (16). Each column represents a unique intersection, as shown by the dark points in the dot-matrix. Bars for each column represent the size of the overlap between each combination. Bars on left represent the size of each unique TRM gene set. (B) Heatmap showing expression levels of our temporal TRM gene signature across T cell subset microarray samples publicly available from Mackay et al. (20). Color scales denote the normalized gene expression (mean zero, unit variance) for each sample. Genes listed in black are unique to our temporal TRM signature. Genes listed in red are those that are shared among all 3 TRM signatures. (C) UMAP embedding of 1,829 skin lymphocytes from a donor 796 days after allogenic hematopoietic stem cell transplantation (42) colored by T cell source (left) and annotated cell type (middle). (right) Dot plot showing the percentage (size of the dot) and scaled expression (color) of select marker genes for the annotated cell types. (D) Host versus donor-derived CD8+ T cells were compared and genes associated with each were ranked (highest rank = genes associated with host-derived CD8+ T cells, lowest rank = genes associated with donor-derived T cells). This ranking was used as input to GSEA using the temporal TRM gene set and the TRM gene set published by Milner et al. (6). (E) Venn diagram of the leading edge genes associated with the GSEA analysis shown in D.