Single-Cell Transcriptomics Reveals Core Regulatory Programs That Determine the Heterogeneity of Circulating and Tissue-Resident Memory CD8+ T Cells

Chen, Yao; Shen, Jian; Kasmani, Moujtaba Y.; Topchyan, Paytsar; Cui, Weiguo

doi:10.3390/cells10082143

Cited by 25 publications

(13 citation statements)

References 53 publications

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“…6 A , Table S1 , and Table S2 ). Consistent with the flow cytometry results, CD4 + T cells in acute MIS-C showed an upregulation of PDCD1 (encoding PD-1) and genes related to tissue residency including CD69 , PRDM1 (encoding for a transcription factor for TRM development; Mackay et al, 2016 ), BATF , and CCL20 ( Chen et al, 2021 ; Kumar et al, 2017 ; Szabo et al, 2019b ).…”

Section: Resultssupporting

confidence: 84%

SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19

Rybkina

Bell

Bradley

et al. 2023

Journal of Experimental Medicine

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SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune responses during acute disease and following recovery in children who developed MIS-C, relative to children who experienced more typical symptoms of COVID-19. T cells in acute MIS-C exhibited transient signatures of activation, inflammation, and tissue residency which correlated with cardiac disease severity, while T cells in acute COVID-19 upregulated markers of follicular helper T cells for promoting antibody production. The resultant memory immune response in recovery showed increased frequencies of virus-specific memory T cells with pro-inflammatory functions in children with prior MIS-C compared to COVID-19 while both cohorts generated comparable antibody responses. Together our results reveal distinct effector and memory T cell responses in pediatric SARS-CoV-2 infection delineated by clinical syndrome, and a potential role for tissue-derived T cells in the immune pathology of systemic disease.

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Section: Resultssupporting

confidence: 84%

SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19

Rybkina

Bell

Bradley

et al. 2023

Journal of Experimental Medicine

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“…This cluster was also characterized by induction of the tissue-residency transcript PDCD1 , encoding PD-1, which has been suggested as a feature of murine tissue-resident brain cells independent of antigen stimulation ( 28, 29 ), and the transcription factor NRF4A1 , important for controlling tissue retention ( 30 ). On the contrary, genes encoding products likely to be involved in tissue-resident cell activation, 11 migration, or retention including ADAM19 ( 31 ), the integrin ITGA4 , and the T cell lineage regulator RORA ( 32 ) was identified for cluster 2. Several transcripts involved in memory differentiation/tissue retention or activation were similarly expressed across clusters, including IL7R, CD69, CD74 and CD82 (Figure 6D and E).…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV2 mRNA-vaccination-induced Immunological Memory in Human Non-Lymphoid and Lymphoid Tissues

Proß

Sattler

Lukassen

et al. 2023

Preprint

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Tissue-resident lymphocytes provide organ-adapted protection against invading pathogens. Whereas their biology has been examined in great detail in various infection models, their generation and functionality in response to vaccination has not been comprehensively analyzed in humans. We therefore studied SARS-CoV2 mRNA-vaccine-specific T cells in surgery specimens of kidney, liver, lung, bone marrow and spleen in comparison to paired blood samples from largely virus-naive individuals. As opposed to lymphoid tissues, non-lymphoid organs harbored significantly elevated frequencies of Spike-specific CD4+ T cells compared to paired peripheral blood showing hallmarks of tissue residency and an expanded memory pool. Organ-derived, vaccine-specific T helper (Th) cells were characterized by increased portions of multifunctional cells over those detected in blood. Single-cell RNA sequencing revealed functional rather than organ-specific clusters of Spike-reactive Th cells, indicating similar diversification programs across tissues. T cell receptor (TCR) repertoire analysis indicated that the TCR sequence is a major determinant of transcriptomic state in tissue-resident, vaccine-specific CD4+ T cells. In summary, our data demonstrate that SARS-CoV2 vaccination entails acquisition of tissue memory and residency features in organs distant from the inoculation site, thereby contributing to our understanding of how local tissue protection might be accomplished.

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“…Trm patrol the gut microenvironment and join the first wave of sentinels during recall responses, with rapid proliferation and function upon encountering their cognate antigen or pathogen (35,36), which are also consistent with our findings on IFNg and TNF (37, 38), as well as other effector molecules (Gzmb, Gzmc, Gzmk and Prf1) that dictate cytotoxic activities. These and other molecular signatures associated with CD8 + Trm provide reassuring evidence that the intestinal CMI mechanisms are complex and highly coordinated (39)(40)(41)(42). It remains challenging to manipulate such responses through the use of subunit or DNA vaccines, as the induction of mucosal immunity in the gut has attracted little attention in ongoing vaccine development.…”

Section: Discussionmentioning

confidence: 99%

Tissue-resident, memory CD8+ T cells are effective in clearing intestinal Eimeria falciformis reinfection in mice

Shi

Zhang²,

Zhang³

et al. 2023

Front. Immunol.

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Eimeria, a cousin of malarial parasites, causes coccidiosis that results in huge losses in the poultry industry. Although live coccidiosis vaccines have been developed and used widely for the successful control of the disease, the mechanism underlying protective immunity remains largely unknown. Using Eimeria falciformis as a model parasite, we observed that tissue-resident memory CD8+ T (Trm) cells accumulated in cecal lamina propria following E. falciformis infection in mice, especially after reinfection. In convalescent mice challenged with a second infection, E. falciformis burden diminished within 48-72 h. Deep-sequencing revealed that CD8+ Trm cells were characterized by rapid up-regulation of effector genes encoding pro-inflammatory cytokines and cytotoxic effector molecules. While FTY720 (Fingolimod) treatment prevented the trafficking of CD8+ T cells in peripheral circulation and exacerbated primary E. falciformis infection, such treatment had no impact on the expansion of CD8+ Trm cells in convalescent mice receiving secondary infection. Adoptive transfer of cecal CD8+ Trm cells conferred immune protection in naïve mice, indicating that these cells provide direct and effective protection against infection. Overall, our findings not only explain a protective mechanism of live oocyst-based anti-Eimeria vaccines but also provide a valuable correlate for assessing vaccines against other protozoan diseases.

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Single-Cell Transcriptomics Reveals Core Regulatory Programs That Determine the Heterogeneity of Circulating and Tissue-Resident Memory CD8+ T Cells

Cited by 25 publications

References 53 publications

SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19

SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19

SARS-CoV2 mRNA-vaccination-induced Immunological Memory in Human Non-Lymphoid and Lymphoid Tissues

Tissue-resident, memory CD8+ T cells are effective in clearing intestinal Eimeria falciformis reinfection in mice

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