ICOS ligand and IL-10 synergize to promote host–microbiota mutualism

Genome-wide association studies have identified ICOSLG, which encodes the inducible costimulator ligand (ICOSLG or ICOSL) as a susceptibility locus for inflammatory bowel disease. ICOSL has been implicated in the enhancement of pattern recognition receptor signaling in dendritic cells, induction of IL-10 production by CD4 T cells, and the generation of high-affinity antibodies to specific antigens—all of which can potentially explain its involvement in gastrointestinal inflammation. Here, we show that murine ICOSL deficiency results in significant enrichment of IL-10–producing CD4 T cells particularly in the proximal large intestine. Transient depletion of IL-10–producing cells from adult ICOSL-deficient mice induced severe colonic inflammation that was prevented when mice were first treated with metronidazole. ICOSL-deficient mice displayed reduced IgA and IgG antibodies in the colon mucus and impaired serum antibody recognition of microbial antigens, including flagellins derived from mucus-associated bacteria of the Lachnospiraceae family. Confirming the synergy between ICOSL and IL-10, ICOSL deficiency coupled with CD4-specific deletion of the Il10 gene resulted in juvenile onset colitis that was impeded when pups were fostered by ICOSL-sufficient dams. In this setting, we found that both maternally acquired and host-derived antibodies contribute to the life anti-commensal antibody repertoire that mediates this protection in early life. Collectively, our findings reveal a partnership between ICOSL-dependent anti-commensal antibodies and IL-10 in adaptive immune regulation of the microbiota in the large intestine. Furthermore, we identify ICOSL deficiency as an effective platform for exploring the functions of anti-commensal antibodies in host–microbiota mutualism.

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The Diversity of Encephalitogenic CD4+ T Cells in Multiple Sclerosis and Its Animal Models

Journal of Clinical Medicine ◽

10.3390/jcm8010120 ◽

2019 ◽

Vol 8 (1) ◽

pp. 120 ◽

Cited By ~ 10

Author(s):

Benjamin Segal

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cd4 T Cells ◽

Association Studies ◽

Critical Role ◽

Genome Wide Association Studies ◽

T Helper ◽

Genome Wide ◽

Disease Modifying Agents ◽

Immunomodulatory Therapies

Autoreactive CD4+ T cells, which target antigens in central nervous system (CNS) myelin, are widely believed to play a critical role in the pathogenesis of multiple sclerosis (MS) in concert with other immune effectors. This theory is supported by data from animal model experiments, genome-wide association studies, and immune profiles of individuals with MS. Furthermore, disease modifying agents that target lymphocytes significantly reduce the rate of MS clinical exacerbations. However, the properties of myelin-reactive CD4+ T cells that are critical for their pathogenic activities are not understood completely. This article reviews the literature on encephalitogenic CD4+ T cells, with an emphasis on T-helper (Th) lineage and cytokine production. An increased understanding of the spectrum of encephalitogenic T cells and how they differ from protective subsets is necessary for the development of the next generation of more effective and safer immunomodulatory therapies customized for individuals with MS and related disorders.

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Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells

PLoS ONE ◽

10.1371/journal.pone.0258316 ◽

2021 ◽

Vol 16 (10) ◽

pp. e0258316

Author(s):

Paul A. Wilson ◽

Sara Santos Franco ◽

Liu He ◽

Nicholas W. Galwey ◽

Jackie Meakin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Ex Vivo ◽

Association Studies ◽

Culture Conditions ◽

Pathway Enrichment Analysis ◽

Genome Wide Association Studies ◽

Isolated Cells ◽

Knock Out

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.

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Faculty Opinions recommendation of Aberrant tissue localization of fungus-specific CD4+ T cells in IL-10-deficient mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1162397.622905 ◽

2009 ◽

Author(s):

Neil Ampel

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Tissue Localization ◽

Deficient Mice

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Genetic architecture of schizophrenia: a review of major advancements

Psychological Medicine ◽

10.1017/s0033291720005334 ◽

2021 ◽

pp. 1-10

Author(s):

Sophie E. Legge ◽

Marcos L. Santoro ◽

Sathish Periyasamy ◽

Adeniran Okewole ◽

Arsalan Arsalan ◽

...

Keyword(s):

Genetic Architecture ◽

Association Studies ◽

Copy Number Variants ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genetic Loci ◽

Significant Enrichment ◽

High Heritability ◽

Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

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Loss of Immunological Tolerance in Gimap5-Deficient Mice Is Associated with Loss of Foxo in CD4+ T Cells

The Journal of Immunology ◽

10.4049/jimmunol.1101206 ◽

2011 ◽

Vol 188 (1) ◽

pp. 146-154 ◽

Cited By ~ 20

Author(s):

H. Ibrahim Aksoylar ◽

Kristin Lampe ◽

Michael J. Barnes ◽

David R. Plas ◽

Kasper Hoebe

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Immunological Tolerance ◽

Deficient Mice

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S1783 Transferred CD4+ T Cells Induce Tight Junction Assembly Through Notch Signaling Pathway in the Distal Colon of RAG1-/- Deficient Mice

Gastroenterology ◽

10.1016/s0016-5085(10)61254-1 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-273

Author(s):

Stephanie Dahan ◽

Jay C. Unkeless ◽

Keren M. Rabinowitz ◽

Paul M. Arnaboldi ◽

Lloyd Mayer

Keyword(s):

T Cells ◽

Tight Junction ◽

Notch Signaling ◽

Signaling Pathway ◽

Cd4 T Cells ◽

Distal Colon ◽

Notch Signaling Pathway ◽

Deficient Mice

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W1604 Transferred CD4+ T Cells Induce IEC Differentiation and Decrease Permeability in the Distal Colon of Rag1-/- Deficient Mice

Gastroenterology ◽

10.1016/s0016-5085(09)63229-7 ◽

2009 ◽

Vol 136 (5) ◽

pp. A-700-A-701

Author(s):

Stephanie Dahan ◽

Andrea P. Martin ◽

M. Cecilia Berin ◽

Sergio A. Lira ◽

Lloyd Mayer

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Distal Colon ◽

Deficient Mice

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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

10.1101/827923 ◽

2019 ◽

Author(s):

Jing Yang ◽

Amanda McGovern ◽

Paul Martin ◽

Kate Duffus ◽

Xiangyu Ge ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

T Cells ◽

Complex Disease ◽

Target Genes ◽

Disease Risk ◽

Association Studies ◽

Dna Interaction ◽

Genome Wide Association Studies ◽

Causal Genes

AbstractGenome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T-cells over 24 hours, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T-cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.

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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

10.1101/2021.05.30.445673 ◽

2021 ◽

Author(s):

Kousuke Mouri ◽

Michael H. Guo ◽

Carl G. de Boer ◽

Greg A. Newby ◽

Matteo Gentili ◽

...

Keyword(s):

T Cells ◽

Autoimmune Disease ◽

Association Studies ◽

Regulatory Element ◽

Genome Wide Association Studies ◽

Expression Of Genes ◽

Human T Cell ◽

Allele Specific ◽

Reporter Assays ◽

Element Activity

Genome-wide association studies have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variant(s) within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naive CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.

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