Heterogeneous generation and expansion of epidermal-resident memory T cells in individuals allergic to nickel.

Pathogenic CD8+ Epidermis-Resident Memory T Cells Displace Dendritic Epidermal T Cells in Allergic Dermatitis

SnapshotDx Quiz: December 2020

Inhibitory checkpoint receptors control CD8+ resident memory T cells to prevent skin allergy

Resident phenotypic memory CD8+ T cells are crucial for immune defense against pathogens. However, little is known about the potential transitions and regulation mechanisms of their function after influenza virus infection and reinfection. In this study, we utilized integrated transcriptome data and in vivo experiments to investigate the key characteristics behind it. Two single-cell RNA sequencing (scRNA-seq) datasets of lung CD8+ T cells and one RNA-seq dataset of lung tissue after infection or reinfection were included. After Seurat procedures classifying CD8+ T subsets, the scCODE algorithm was used to identify the differentially expressed genes for GSVA, GO, and KEGG pathway enrichment. Monocle 3 and CellChat were used to infer pseudotime cell trajectory and cell interactions. The ssGSEA method was used to estimate the relative proportions of immune cells. The findings were confirmed with a mouse model via flow cytometry and RT-PCR analysis. Our study refined the landscape of CD8+ T-cell subsets in the lung, showing that CD8+ Trm cells accumulated in the lung within 14 days after influenza infection. The classical CD8+ Trm cells co-expressed a high level of CD49a and even maintained 90 days after primary infection. The ratio of CD8+ Trm cells decreased 1 day after influenza reinfection, which may be parallel with their potential transition into effector types, as observed in trajectory inference analysis. KEGG analysis suggested that PD-L1 expression and PD-1 checkpoint pathway were upregulated in CD8+ Trm cells on day 14 after infection. GO and GSVA analyses revealed that PI3K-Akt-mTOR and type I interferon signaling pathways were enriched in CD8+ Tem and Trm cells after reinfection. Additionally, CCL signaling pathways were involved in cell interaction between CD8+ Trm cells and other cells, with Ccl4-Ccr5 and Ccl5-Ccr5 ligand/receptor pairs being important between CD8+ Trm and other memory subsets after infection and reinfection. Our data suggest that resident memory CD8+ T cells with CD49a co-expression account for a large proportion after influenza infection, and they can be rapidly reactivated against reinfection. Function differences exist in CD8+ Trm and Tem cells after influenza infection and reinfection. Ccl5-Ccr5 ligand/receptor pair is important in cell interactions between CD8+ Trm and other subsets.

Nickel allergy in the United States: A public health issue in need of a “nickel directive”

Donor T-Derived Memory Progenitors Differentiated into CD103+/- CXCR6+CD4+ Tissue-Resident T Cell Subsets Driven Cutaneous Chronic Graft-Versus-Host Disease

Allergic skin diseases

Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells

Characterization of Th17 tissue-resident memory cells in non-inflamed intestinal tissue of Crohn's disease patients

Central memory T (TCM) cells in lymph nodes (LNs) and resident memory T (TRM) cells in peripheral tissues have distinct roles in protective immunity. Both are generated after primary infections, but their clonal origins have been unclear. To address this question, we immunized mice through the skin with a protein antigen, a chemical hapten, or a non-replicating poxvirus. We then analyzed antigen-activated T cells from different tissues using high-throughput sequencing (HTS) of the gene encoding the T cell receptor (TCR) β-chain (Trb, also known as Tcrb) using CDR3 sequences to simultaneously track thousands of unique T cells. For every abundant TRM cell clone generated in the skin, an abundant TCM cell clone bearing the identical TCR was present in the LNs. Thus, antigen-reactive skin TRM and LN TCM cell clones were derived from a common naive T cell precursor after skin immunization, generating overlapping TCR repertoires. Although they bore the same TCR, TRM cells mediated rapid contact hypersensitivity responses, whereas TCM cells mediated delayed and attenuated responses. Studies in human subjects confirmed the generation of skin TRM cells in allergic contact dermatitis. Thus, immunization through skin simultaneously generates skin TRM and LN TCM cells in similar numbers from the same naive T cells.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

In allergic contact dermatitis (ACD) and contact hypersensitivity (CHS), the healed skin shows greater swelling than the naïve skin in the same individual upon re-exposure to the same hapten. This “local skin memory” (LSM) in healed skin was maintained for a prolonged period of time and mediated by skin CD8+-resident memory T (TRM) cells in C57BL/6 mice. However, the number of CD4+ T cells is elevated in ACD-healed human skin, and the contribution of CD4+ TRM cells to the formation of LSM currently remains unclear. We herein demonstrated that immediately after CHS subsided, the healed skin in BALB/c mice showed an accumulation of hapten-specific CD4+ and CD8+ TRM cells, with a predominance of CD4+ TRM cells. The presence of CD4+ or CD8+ TRM cells in the healed skin was sufficient for the induction of a flare-up reaction upon a re-challenge. The CD4+ and CD8+ TRM cells both produced interferon-γ and tumor necrosis factor early after the re-challenge. Moreover, while CD8+ TRM cells gradually decreased over time and were eventually lost from the healed skin at 40–51 weeks after the resolution of CHS, the CD4+ TRM cell numbers remained elevated during this period. The present results indicate that the long-term maintenance of LSM is mediated by CD4+ TRM cells, and thus CD4+ TRM cells are an important target for the treatment of recurrent human ACD.

Background Crohn's disease (CD) is a chronic inflammatory disorder affecting the bowel wall. Tissue-resident memory T (Trm) cells are implicated in CD, yet their characteristics remain unclear. We aimed to investigate the transcriptional profiles and functional characteristics of Trm cells in the small bowel of CD and their interactions with immune cells. Methods Seven patients with CD and four with ulcerative colitis as controls were included. Single-cell RNA sequencing and paired T cell receptor sequencing assessed T cell subsets and transcriptional signatures in lamina propria (LP) and submucosa/muscularis propria-enriched fractions (SM/MP) from small bowel tissue samples. Results We identified 58,123 T cells grouped into 16 populations, including the Th17 Trm, CD4+ Trm, and CD8+ Trm clusters. In patients with CD, we identified Trm cells with a Th17 signature (termed Th17 Trm) in the bowel, demonstrating significantly increased proportions of the Th17 Trm cluster in both the LP and SM/MP areas. The Th17 Trm cluster demonstrated heightened expression of canonical tissue-residency marker genes (ITGAE, ITGA1, and CXCR6) along with elevated levels of IL17A, IL22, CCR6, and CCL20. The clonal expansion of Th17 Trm cells in CD was accompanied by enhanced transmural dynamic potential, as indicated by significantly higher migration scores. CD-prominent Th17 Trm cells displayed an increased interferon gamma (IFNγ)-related signature linked with STAT1 activation, inducing chemokines (i.e., CXCL10, CXCL8, and CXCL9) in myeloid cells. Conclusion Our findings underscored the elevated Th17 Trm cells throughout the small bowel in CD, contributing to disease pathogenesis through IFNγ induction and subsequent chemokine production in myeloid cells.

Tissue-resident memory CD8+ T (Trm) cells mediate potent local innate and adaptive immune responses and play a central role against solid tumors. However, whether Trm cells cross-talk with dendritic cells (DCs) to support anti-tumor immunity remains unclear. Here we show that antigen-specific activation of skin Trm cells leads to maturation and migration to draining lymph nodes of cross-presenting dermal DCs. Tumor rejection mediated by Trm cells triggers the spread of cytotoxic CD8+ T cell responses against tumor-derived neo- and self-antigens via dermal DCs. These responses suppress the growth of intradermal tumors and disseminated melanoma lacking the Trm cell-targeted epitope. Moreover, analysis of RNA sequencing data from human melanoma tumors reveals that enrichment of a Trm cell gene signature associates with DC activation and improved survival. This work unveils the ability of Trm cells to amplify the breath of cytotoxic CD8+ T cell responses through DCs, thereby strengthening anti-tumor immunity.

CD8+ Skin-Resident Memory T Cells Require TCR Signaling for their Persistence in a Mouse Model of Allergic Contact Dermatitis.