Biology subjects

Gommerman, J. L.

Publications and source records attributed to Gommerman, J. L..

6 recordsLinked to original sources

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

Bona fide cytotoxic iNKT cells with superior antitumour responses identified in mice and humans

Adoptive cell therapies (ACT) using unmodified or engineered invariant Natural Killer T (iNKT) cells are in clinical trials for cancer treatment. While promising, outcomes are still suboptimal, possibly due to iNKT cell heterogeneity. This study identified unique iNKT cell populations with strong cytotoxic activity in mice and humans. In mice, iNKT1c cells showed potent CD1d-dependent and -independent antitumor functions, with responses influenced by NK receptors. IL-15 enhances their cytolytic activity, while retinoic acid is essential for their generation. In humans, terminally differentiated CD57+ iNKT cells showed marked NK-receptor expression and most effectively killed C1R tumor cells in vitro. These cells appeared activated/exhausted within tumors of non-small cell lung cancer patients. Additionally, a central memory-like CD62L+ CD4- iNKT subset efficiently expanded and generated cytotoxic CD57+ iNKT cells in vitro, making them an appealing candidate for ACT. This study paves the way for the design of more effective iNKT cell-based immunotherapies.

immunology↗

bioRxiv2024

Mining for microbial metabolites associated with disease progression in an age-dependent model of experimental autoimmune encephalomyelitis

Age is a risk factor for the neurological decline and physical disability that characterize progressive multiple sclerosis (MS). The intestinal microbiota and the bioactive compounds it produces can influence aging, immunity, and the central nervous system (CNS). Here, we use an experimental autoimmune encephalomyelitis (EAE) model that mimics features of progressive MS in aged, but not young, mice to address the intersection of age and the microbiota on EAE outcomes. Although the microbiota of SJL/J mice aged under controlled laboratory conditions does not promote an aged non-remitting EAE phenotype, young mice harboring heterochronic human fecal microbiota transplants (hFMT) developed a range of EAE phenotypes. Metabolomic profiling of mice colonized with an aged hFMT that promoted non-remitting EAE indicated a severe reduction in circulating levels of the microbiota-derived tryptophan metabolite indole 3-propionic acid (IPA). IPA-supplementation enforced remission in mice colonized with the non-remitting hFMT, demonstrating the utility of this in vivo pipeline for discovering metabolites associated with progressive MS-like disease. SummaryThe microbiota is a critical determinant of disease susceptibility in mouse models of MS. Here, Pu & Fettig et al. demonstrate that disease outcomes (remitting or non-remitting) are microbiota-responsive, and describe an in vivo pipeline that can be mined for microbial metabolites with therapeutic potential for progressive MS.

immunology↗

bioRxiv2021

Age related susceptibility to grey matter demyelination and neurodegeneration is associated with meningeal neutrophil accumulation in an animal model of Multiple Sclerosis

People living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils.

immunology↗

bioRxiv2020

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Here we show that the eIF2 kinase HRI potentiates the autophagic clearance of cytosolic protein aggregates when the UPS is inhibited. In cells silenced for HRI, proteasome inhibition resulted in accumulation of aggresomes and ubiquitinated proteins, as well as cytotoxicity. Moreover, silencing of HRI resulted in cytotoxic accumulation of over-expressed -synuclein, a protein known to aggregate in Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy. In agreement, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded -synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to -synucleinopathies in humans where it may contribute to impaired micturition and/or constipation. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response (cUPR) that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

cell biology↗

bioRxiv2019

Perinatal Programming of Mucosal Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult

Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyers patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin - LT) at different developmental stages. We found that LT-beta receptor (LT{beta}R) signalling in utero programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, in utero LT{beta}R signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how in utero LT{beta}R signalling impacts mucosal immune responses during adulthood. One Sentence SummaryEarly life LT{beta}R signalling is critical for programming the mesenteric lymph node stromal cell environment, impacting both antibody isotype switching to IgA and the differentiation of IgA+ antibody secreting cells. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/557652v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@4780dborg.highwire.dtl.DTLVardef@5cbe85org.highwire.dtl.DTLVardef@e0465eorg.highwire.dtl.DTLVardef@2bcae6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗