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Transcriptional programming of CD4⁺ T_RM differentiation in viral infection balances effector- and memory-associated gene expression.

ABSTRACT: After resolution of infection, T cells differentiate into long-lived memory cells that recirculate through secondary lymphoid organs or establish residence in tissues. In contrast to CD8⁺ tissue-resident memory T cells (T_RM), the developmental origins and transcriptional regulation of CD4⁺ T_RM remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profiles of CD4⁺ T_RM in the small intestine (SI) responding to acute viral infection, revealing a shared gene expression program and chromatin accessibility profile with circulating T_H1 and the progressive acquisition of a mature T_RM program. Single-cell RNA sequencing identified heterogeneity among established CD4⁺ T_RM, which were predominantly located in the lamina propria, and revealed a population of cells that coexpressed both effector- and memory-associated genes, including the transcriptional regulators Blimp1, Id2, and Bcl6. T_H1-associated Blimp1 and Id2 and T_FH-associated Bcl6 were required for early T_RM formation and development of a mature T_RM population in the SI. These results demonstrate a developmental relationship between T_H1 effector cells and the establishment of early T_RM, as well as highlighted differences in CD4⁺ versus CD8⁺ T_RM populations, providing insights into the mechanisms underlying the origins, differentiation, and persistence of CD4⁺ T_RM in response to viral infection.

SUBMITTER: Nguyen QP

PROVIDER: S-EPMC10350289 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Transcriptional programming of CD4+ TRM differentiation in viral infection balances effector- and memory-associated gene expression.

Nguyen Quynh P QP Takehara Kennidy K KK Deng Tianda Z TZ O'Shea Shannon S Heeg Maximilian M Omilusik Kyla D KD Milner J Justin JJ Quon Sara S Pipkin Matthew E ME Choi Jinyong J Crotty Shane S Goldrath Ananda W AW

Science immunology 20230512 83

After resolution of infection, T cells differentiate into long-lived memory cells that recirculate through secondary lymphoid organs or establish residence in tissues. In contrast to CD8+ tissue-resident memory T cells (TRM), the developmental origins and transcriptional regulation of CD4+ TRM remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profiles of CD4+ TRM in the small intestine ...[more]

PMID: 37172104

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Project description:BackgroundIn T cells, the Kv1.3 and the KCa3.1 potassium channels regulate the membrane potential and calcium homeostasis. Notably, during TEM cell activation, the number of Kv1.3 channels on the cell membrane dramatically increases. Kv1.3 blockade results in inhibition of Ca2+ signaling in TEM cells, thus eliciting an immunomodulatory effect. Among the naturally occurring peptides, the Vm24 toxin from the Mexican scorpion Vaejovis mexicanus is the most potent and selective Kv1.3 channel blocker known, which makes it a promissory candidate for its use in the clinic. We have shown that addition of Vm24 to TCR-activated human T cells inhibits CD25 expression, cell proliferation and reduces delayed-type hypersensitivity reactions in a chronic inflammation model. Here, we used the Vm24 toxin as a tool to investigate the molecular events that follow Kv1.3 blockade specifically on human CD4+ TEM cells as they are actively involved in inflammation and are key mediators of autoimmune diseases.MethodsWe combined cell viability, activation, and multiplex cytokine assays with a proteomic analysis to identify the biological processes affected by Kv1.3 blockade on healthy donors CD4+ TEM cells, following TCR activation in the presence or absence of the Vm24 toxin.ResultsThe peptide completely blocked Kv1.3 channels currents without impairing TEM cell viability, and in response to TCR stimulation, it inhibited the expression of the activation markers CD25 and CD40L (but not that of CD69), as well as the secretion of the pro-inflammatory cytokines IFN-γ and TNF and the anti-inflammatory cytokines IL-4, IL-5, IL-9, IL-10, and IL-13. These results, in combination with data from the proteomic analysis, indicate that the biological processes most affected by the blockade of Kv1.3 channels in a T cell activation context were cytokine-cytokine receptor interaction, mRNA processing via spliceosome, response to unfolded proteins and intracellular vesicle transport, targeting the cell protein synthesis machinery.ConclusionsThe Vm24 toxin, a highly specific inhibitor of Kv1.3 channels allowed us to define downstream functions of the Kv1.3 channels in human CD4+ TEM lymphocytes. Blocking Kv1.3 channels profoundly affects the mRNA synthesis machinery, the unfolded protein response and the intracellular vesicle transport, impairing the synthesis and secretion of cytokines in response to TCR engagement, underscoring the role of Kv1.3 channels in regulating TEM lymphocyte function.

Dataset Information

Transcriptional programming of CD4⁺ T_RM differentiation in viral infection balances effector- and memory-associated gene expression.

Publications

Transcriptional programming of CD4<sup>+</sup> T<sub>RM</sub> differentiation in viral infection balances effector- and memory-associated gene expression.

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