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Tet2 deletion in CD4+ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses

ABSTRACT: Tet2 deletion in CD4+ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses

PROVIDER: PRJNA1000627 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25468563_1.fastq.gz	Fastqsanger.gz
	SRR25468563_2.fastq.gz	Fastqsanger.gz
	SRR25468564_1.fastq.gz	Fastqsanger.gz
	SRR25468564_2.fastq.gz	Fastqsanger.gz
	SRR25468565_1.fastq.gz	Fastqsanger.gz

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Tet2 deletion in CD4+ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses

Project description:Following viral clearance, antigen-specific CD4+ T cells contract and form a pool of distinct Th1 and Tfh memory cells that possess unique epigenetic programs, allowing them to rapidly recall their specific effector functions upon rechallenge. DNA methylation programing mediated by the methylcytosine dioxygenase Tet2 contributes to balancing Th1 and Tfh cell differentiation during acute viral infection, however the role of Tet2 in CD4+ T cell memory formation and recall is unclear. Using adoptive transfer models of antigen-specific WT andTet2KO CD4+ T cells, we find that Tet2 is required for full commitment of CD4+ T cells to the Th1 lineage and that in the absence of Tet2, memory cells preferentially recall a Tfh like phenotype with enhanced expansion upon secondary challenge. These findings demonstrate an important role for Tet2 in enforcing lineage commitment and programing proliferation potential, and highlight the potential of targeting epigenetic programing to enhance adaptive immune responses.

2023-08-11 | GSE239724 | GEO

Tet2 deletion in CD4+ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses to viral rechallenge.

Project description:Following viral clearance, antigen-specific CD4+ T cells contract and form a pool of distinct Th1 and Tfh memory cells that possess unique epigenetic programs, allowing them to rapidly recall their specific effector functions upon rechallenge. DNA methylation programing mediated by the methylcytosine dioxygenase Tet2 contributes to balancing Th1 and Tfh cell differentiation during acute viral infection; however, the role of Tet2 in CD4+ T cell memory formation and recall is unclear. Using adoptive transfer models of antigen-specific wild type and Tet2 knockout CD4+ T cells, we find that Tet2 is required for full commitment of CD4+ T cells to the Th1 lineage and that in the absence of Tet2, memory cells preferentially recall a Tfh like phenotype with enhanced expansion upon secondary challenge. These findings demonstrate an important role for Tet2 in enforcing lineage commitment and programing proliferation potential, and highlight the potential of targeting epigenetic programing to enhance adaptive immune responses.

| S-EPMC10483640 | biostudies-literature

Tet2 coordinates with Foxo1 and Runx1 to balance T follicular helper cell and T helper 1 cell differentiation.

Project description:In response to various types of infection, naïve CD4+ T cells differentiate into diverse helper T cell subsets; however, the epigenetic programs that regulate differentiation in response to viral infection remain poorly understood. Demethylation of CpG dinucleotides by Tet methylcytosine dioxygenases is a key component of epigenetic programing that promotes specific gene expression, cellular differentiation, and function. We report that following viral infection, Tet2-deficient CD4+ T cells preferentially differentiate into highly functional germinal center T follicular helper (TFH) cells that provide enhanced help for B cells. Using genome-wide DNA methylation and transcription factor binding analyses, we find that Tet2 coordinates with multiple transcription factors, including Foxo1 and Runx1, to mediate the demethylation and expression of target genes, including genes encoding repressors of TFH differentiation. Our findings establish Tet2 as an important regulator of TFH cell differentiation and reveal pathways that could be targeted to enhance immune responses against infectious disease.

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A novel adjuvant formulation induces robust Th1/Th17 memory and mucosal recall responses in Non-Human Primates

Project description:After clean drinking water, vaccination is the most impactful global health intervention. However, development of new vaccines against difficult-to-target diseases is hampered by the lack of diverse adjuvants for human use. Of particular interest, none of the currently available adjuvants induce Th17 cells. Here, we develop and test an improved liposomal adjuvant, termed CAF®10b, that incorporates a TLR-9 agonist. In a head-to-head study in non-human primates (NHPs), immunization with antigen adjuvanted with CAF®10b induced significantly increased antibody and cellular immune responses compared to previous CAF® adjuvants, already in clinical trials. This was not seen in the mouse model, demonstrating that adjuvant effects can be highly species specific. Importantly, intramuscular immunization of NHPs with CAF®10b induced robust Th17 responses that were observed in circulation half a year after vaccination. Furthermore, subsequent instillation of unadjuvanted antigen into the skin and lungs of these memory animals led to significant recall responses including transient local lung inflammation observed by Positron Emission Tomography-Computed Tomography (PET-CT), elevated antibody titers, and expanded systemic and local Th1 and Th17 responses, including >20% antigen-specific T cells in the bronchoalveolar lavage. Overall, CAF®10b demonstrated an adjuvant able to drive true memory antibody, Th1 and Th17 vaccine-responses across rodent and primate species, supporting its translational potential.

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Multi-scale epigenomic priming of inflammatory genes enables rapid recall in human memory T helper cells [ChIP-seq]

Project description:Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate. How memory T cells efficiently ‘recall’ an inflammatory transcriptional program remains unclear. Here, we show that primary human CD4+ memory T helper (Th) cells carry three distinct activation-inducible recall gene modules that drive metabolic adaptation, T cell activation and inflammatory cytokine production. Enhancer elements controlling recall genes were epigenetically primed through the local maintenance of transcription-permissive chromatin in resting memory Th cells. At the three-dimensional level, recall genes clustered in transcriptionally permissive subnuclear compartments and resided in topologically associating domains (‘memory TADs’), in which activation-associated promoter-enhancer interactions were pre-formed. This primed epigenomic landscape was exploited by AP-1 transcription factors - including MAF - to promote rapid transcriptional activation. Finally, recall genes and their enhancers were linked to memory Th cell dysfunction in chronic inflammatory disease. Together, our results implicate multi-scale epigenomic priming - comprising a specialized three-dimensional chromatin organization - as a key mechanism underlying immunological memory.

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Multi-scale epigenomic priming of inflammatory genes enables rapid recall in human memory T helper cells [RNA-seq]

2023-08-08 | GSE210958 | GEO

Impact of Lef1 overexpression on follicular helper T (Tfh) differentiation

Project description:Comparison of transcriptome between GFP-RV+ Th1 cells and Lef1-RV+ Th1 cells B6 mice received GFP-RV+ or Lef1-RV+ LCMV gp specific TCRtg Smarta cells and were infected with LCMV. On four days after infection, splenocytes were collected to sort CXCR5- Th1 cells per genotype. Contributor: LIAI RNAi Center (LIAI)

2015-07-27 | E-GEOD-67335 | biostudies-arrayexpress

Impact of Lef1 overexpression on follicular helper T (Tfh) differentiation

Project description:Comparison of transcriptome between GFP-RV+ Th1 cells and Lef1-RV+ Th1 cells

2015-07-27 | GSE67335 | GEO

Interferon gamma suppresses T follicular helper cells and antibody responses upon viral infection

Project description:Humoral and cellular immunity upon viral infections usually co-exist; however, sometimes, one of the two responses emerges as dominant and is responsible for most of the antiviral activity. For example, infection with lymphocytic choriomeningitis virus (LCMV) induces very strong cellular responses, but weak and inefficient neutralizing Ab (nAb) responses. Lack of nAb responses is an important issue for complete clearance of LCMV and other similar viruses, which in some instances tend to establish chronic infections. Recent work from our group has shown that this unbalance is observed also at the level of CD4 T cells responses, with subcutaneous LCMV infection leading almost exclusively to TH1 but no TFH differentiation. Here, we report that LCMV-induced TH1 cells are heterogeneous and comprise a Tcf-1+ subset and a GzmB+ subset. We found that none of the subsets is dependent on the major TH1-polarizing cytokine IL-12. Instead, IFN-gamma (IFN-g) was found to promote the development of GzmB+ cells and to suppress the commitment of the Tcf-1+ population into fully differentiated TFH. As a result, blockade of IFN-g led to a rescue in the TFH population, germinal center B cells and antibody responses. Our results shed light on new mechanisms underlying the inefficient nAbs production in response to non-cytopathic viruses such as LCMV and are promising for the design of new vaccination strategies.

2025-03-25 | GSE239968 | GEO

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