Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection

Snell, Laura M.; Xu, Wenxi; Abd-Rabbo, Diala; Boukhaled, Giselle M.; Guo, Mengdi; MacLeod, Bethany; Elsaesser, Heidi; Hezaveh, Kebria; Alsahafi, Nirmin; Lukhele, Sabelo; Nejat, Sara; Prabhakaran, Ramanandan; Epelman, Slava; McGaha, Tracy L.; Brooks, David G.

doi:10.1038/s41590-021-01060-7

Cited by 31 publications

(35 citation statements)

References 69 publications

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“…However, CD4 + T cells progress through multiple Th differentiation states in the context of tumors, leading to a unique requirement to consider functional changes in molecular programs within the context of specific Th differentiation states. Our data demonstrate that the majority of tumor-specific CD4 + T cells differentiated into Th1 cells, consistent with a previous report that the inhibiting of PD-L1 restored CD4 + Th1 cell amplification rapidly, enhancing CD4 + Th1 cytokine production and cytotoxic killing capacity during chronic infection in mice ( 48 ). Further, our finding that SMARTA cell efficacy was not reduced following FYT720 administration is of great importance.…”

Section: Discussionsupporting

confidence: 93%

Tumor-Specific CD4+ T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4– T Cells

Wang

Lin

et al. 2022

Front. Immunol.

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Cytotoxic CD8+ T cells are the main focus of efforts to understand anti-tumor immunity and immunotherapy. The adoptive transfer of tumor-reactive cytotoxic CD8+ T lymphocytes expanded and differentiated in vitro has long been considered the primary strategy in adaptive anti-tumor immunity, however, the majority of the transferred tumor antigen-specific CD8+ T cells differentiated into CD39+CD69+ exhausted progenies, limiting its effects in repressing tumor growth. Contrarily, less attention has been addressed to the role of CD4+ T cells during tumorigenesis. Using a mouse model of metastatic melanoma, we found that transferring tumor-specific CD4+ T cells into recipients induces substantial regression of the established metastatic tumors. Notably, in vitro activated CD4+ T cells developed into cytotoxic CD4- T cells in vivo and get exhausted gradually. The blockade of PD-L1 signaling resulted in an expansion of tumor specific CD4+ T cells, which could better control the established metastatic melanoma. Moreover, the tumor-specific memory CD4+ T cell can prevent mice from tumor metastasis, and the tumor-specific effector CD4+ T cells can also mitigate the established metastatic tumor. Overall, our findings suggest a novel mechanism of CD4+ T cells in curtailing tumor metastasis and confirm their therapeutic role in combination with PD-L1 blockade in cancer immunotherapy. Hence, a better understanding of cytotoxic CD4- T cell-mediated tumor regression could provide an alternative choice for patients exhibiting suboptimal or no response to CD8+ T cell-based immunotherapies.

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Section: Discussionsupporting

confidence: 93%

Tumor-Specific CD4+ T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4– T Cells

Wang

Lin

et al. 2022

Front. Immunol.

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“…S1). 18 In CLP-induced septic model, the abovementioned changes in hepatic cellular composition were consistently observed using FCM (Fig. S1A-C).…”

Section: Single-cell Rna-seq Defines Hepatic Cellular Composition And...mentioning

confidence: 65%

Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia

Sun

Liu

et al. 2022

Journal of Hepatology

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“… ( A ) UMAP embeddings of projected scRNA-seq data of virus-specific (SMARTA) CD4 + T cells isolated from anti-PDL1 treated or isotype control animals with LCMV chronic infection at day 33 p.i., from the study by Snell et al, 2021 . ( B ) Average expression profiles for a panel of marker genes in the six most represented reference cell states, for the reference and the two conditions (isotype vs. anti-PDL1 treated).…”

Section: Resultsmentioning

confidence: 99%

“…( D ) UMAP embeddings for projected scRNA-seq data of Bcl6- and Prdm1-deficient virus-specific CD4 + T cells isolated 7 days after acute infection with LCMV Armstrong (data from Ciucci et al, 2022 ). ( E ) UMAP embeddings for projected scRNA-seq data of virus-specific CD4 + T cells isolated 33 days after chronic infection with LCMV Clone13, in animals treated with anti-PDL1 or isotype control (data from Snell et al, 2021 ). Barplots in the bottom row indicate the percentage of cells projected in each reference subtype.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we aimed at using our reference map to interpret the effect of immunotherapies. To this end, we projected scRNA-seq data of virus-specific CD4 + T cells isolated from mice chronically infected with LMCV, after treatment with an anti-PD-L1 antibody ( Snell et al, 2021 ). While control samples showed a similar subtype distribution to our late chronic samples ( Figure 5E , Figure 3C ), anti-PD-L1 treatment increased the relative proportion of Th1 effectors ( Figure 5E ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A CD4+ T cell reference map delineates subtype-specific adaptation during acute and chronic viral infections

Andreatta

Tjitropranoto

Sherman

et al. 2022

eLife

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CD4+ T cells are critical orchestrators of immune responses against a large variety of pathogens, including viruses. The multifaceted roles of CD4+ T cells, including their help to innate cells, CD8+ T and B cells and their support for long-lived immunity rely on a profound functional heterogeneity. While multiple CD4+ T cell subtypes and their key transcriptional regulators have been identified, there is a lack of consistent definition for CD4+ T cell transcriptional states. In addition, the progressive changes affecting CD4+ T cell subtypes during and after immune responses remain poorly defined. Taking advantage of single-cell transcriptomics, efficient computational methods, and robust animal models, we characterize the transcriptional landscape of CD4+ T cells responding to self-resolving and chronic viral infections. We build a comprehensive map of virus-specific CD4+ T cells and their evolution over time, and identify six major distinct cell states that are consistently observed in acute and chronic infections in mice. During the course of acute infections, T cell composition progressively changes from effector to memory states, with subtype-specific gene modules and kinetics. Conversely, T cells in persistent infections fail to transition from effector to memory states, and acquire distinct, chronicity-associated transcriptional programs. By single-cell T cell receptor (TCR) sequencing analysis, we characterize the clonal structure of virus-specific CD4+ T cells across individuals and T cell subtypes. We find that virus-specific CD4+ T cell responses are essentially private across individuals and that most T cells differentiate into both Tfh and Th1 subtypes irrespective of their TCR, in both acute and chronic infections. Finally, we show that our CD4+ T cell map can be used as a reference to accurately interpret cell states in external single-cell datasets across tissues and disease models. Overall, this study describes a previously unappreciated level of adaptation of the transcriptional states of CD4+ T cells responding to viruses and provides a new computational resource for CD4+ T cell analysis, available online at https://spica.unil.ch.

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Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection

Cited by 31 publications

References 69 publications

Tumor-Specific CD4+ T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4– T Cells

Tumor-Specific CD4+ T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4– T Cells

Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia

A CD4+ T cell reference map delineates subtype-specific adaptation during acute and chronic viral infections

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