Biology subjects

Watts, T. H.

Publications and source records attributed to Watts, T. H..

3 recordsLinked to original sources

bioRxiv2026

T cell intrinsic 4-1BB signals induce Prdm16 to increase effector and memory T cell numbers during respiratory influenza infection

TNFR superfamily members such as 4-1BB sustain T cell responses to control virus infections or tumors. However, the precise role of 4-1BB during an acute infection remains incompletely understood. Here we used mixed bone marrow chimeras and transcriptome analysis to show that intrinsic 4-1BB signaling in lung T cells during influenza A virus (IAV) infection induces the transcriptional coregulator PR domain containing 16 (Prdm16), known for its role in regulating mitochondrial biology in other cell types. T cell-specific deletion of Prdm16 reduced the number of Ag-specific CD8 T cells, with a larger effect on T cells in the lung parenchyma compared to the vasculature or lymphoid tissues. Conversely, Prdm16 overexpression in T cells increased effector and memory CD8 T cell accumulation during IAV infection. Single nuclei transcriptomics suggested that Prdm16 allows the accumulation of T cells with high protein translation and mitochondrial activity. Prdm16 increased genes associated with oxidative phosphorylation and mitophagy. Consistently, Prdm16 overexpressing cells had more compact mitochondrial cristae, which has been associated with more efficient electron transport. Prdm16 also repressed some genes, including Herpes virus entry mediator, which can inhibit T cell responses through B and T lymphocyte attenuator. These findings reveal a 4-1BB-Prdm16 axis that is induced in T cells during viral infection to support T cell accumulation and memory formation.

immunology↗

bioRxiv2025

Unconventionally primed type 1 follicular helper T cells are required for long-lived IgA plasma cell development following mucosal viral infection

Although IgA+ long-lived plasma cells (LLPCs) generated following mucosal viral infection provide durable protection against reinfection, little is known about their generation. Here, we show that oral RV infection induces gut-resident LLPCs that produce highly mutated protective IgA. Unlike RV-specific IgG+ LLPCs, IgA+ LLPCs were generated independently of MHCII expression by dendritic cells - rather MHCII expression by B cells was both necessary and sufficient. B cell MHCII was also sufficient to induce a unique population of T-bet+ follicular helper T (TFH1) cells which were crucial for RV-specific IgA+ LLPC accumulation in the gut via IFN{gamma}- and CXCR3-dependent mechanisms. Similar to RV infection, TFH1 cells were required for influenza-specific IgA response. However, unlike RV infection, B cell MHCII was not sufficient to induce influenza-specific IgA+ LLPCs, suggesting the operation of mucosal site-specific priming mechanisms. Collectively, our data reveal that unconventionally primed TFH1 cells support IgA responses to mucosal viral infections.

immunology↗

bioRxiv2024

STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a sensor of cytosolic DNA, orchestrates the production of pro-inflammatory cytokines, chemokines, and type I interferons (IFN-I), thereby contributing to spontaneous tumor surveillance. Intratumoral delivery of synthetic STING agonists induces IFN-I dependent tumor regression in preclinical cancer models and is being tested clinically. In this study, we investigate the role of monocytic lineage (MCs) cells in response to STING agonist induced IFN-I signaling. We show that CCR2-deficient mice, lacking inflammatory MCs in the periphery, or Lyz2-Cre-IFNAR1fl/fl mice in which IFN-I signaling in monocytes is reduced, exhibit impaired responses to STING agonist therapy of MC38 and/or B16F10 tumors. STING agonist treatment induced CCR5-dependent migration of MCs carrying tumor antigen from the tumor to the lymph nodes. Single-cell RNA sequencing of CD45+ cells from lymph nodes and tumors of mice in which half the hematopoietic cells lack the interferon alpha/beta receptor 1 (IFNAR1) revealed that STING agonist therapy induces intrinsic IFNAR1-dependent acquisition of an inflammatory monocytic cell phenotype distinct from inflammatory cDC and a reduction in macrophages with a pro-tumor TGF{beta}/angiogenesis transcriptome. IL-18 - IL-18R1 interaction was the top predicted interaction between monocytic lineage cells and CD8+T cells or NK cells. Blocking IL-18 reduced IFN-{gamma} production by CD8 T cells in LNs and decreased the therapeutic efficacy of STING agonist treatment in CCR2+/+ but not in CCR2-/- mice. These findings support a pivotal role for IL-18 producing inflammatory monocytic lineage cells in CD8 T cell control of melanoma following STING agonist treatment.

immunology↗