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MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4⁺ T cells in vivo.

ABSTRACT: There has been growing interest in the role of B cells in antitumour immunity and potential use in adoptive cellular therapies. To date, the success of such therapies is limited. The intrinsic capacity of B cells to specifically activate tumour-specific CD4+ T cells in vivo via TCR-dependent interactions remains poorly defined. We have developed an in vivo tumour model that utilizes MHCII I-E restriction which limits antigen presentation to tumour-specific CD4 T cells to either tumour-specific B cells or host myeloid antigen presenting cells (APCs) in lymphopenic RAG-/-mice. We have previously shown that these naive tumour-specific CD4+ T cells can successfully eradicate established tumours in this model when activated by host APCs. When naïve tumour-specific B cells are the only source of I-E+ APC, very limited proliferation of naïve CD4+ T cells is observed, whereas host I-E+ APCs are potent T cell activators. B cells pre-activated with an anti-CD40 agonistic antibody in vivo support increased T cell proliferation, although far less than host APCs. CD4+ T cells that have already differentiated to an effector/central memory phenotype proliferate more readily in response to naïve B cells, although still 100-fold less than in response to host APCs. This study demonstrates that even in a significantly lymphopenic environment, myeloid APCs are the dominant primary activators of tumour-specific T cells, in contrast to the very limited capacity of tumour-specific B cells. This suggests that future anti-tumour therapies that incorporate activated B cells should also include mechanisms that activate host APCs.

SUBMITTER: Guy TV

PROVIDER: S-EPMC10730170 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4+ T cells in vivo.

Guy Thomas V TV Terry Alexandra M AM McGuire Helen M HM Shklovskaya Elena E Fazekas de St Groth Barbara B

Oncoimmunology 20231210 1

There has been growing interest in the role of B cells in antitumour immunity and potential use in adoptive cellular therapies. To date, the success of such therapies is limited. The intrinsic capacity of B cells to specifically activate tumour-specific CD4+ T cells in vivo via TCR-dependent interactions remains poorly defined. We have developed an in vivo tumour model that utilizes MHCII I-E restriction which limits antigen presentation to tumour-specific CD4 T cells ...[more]

PMID: 38125720

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Project description:Background/objectivesAlthough obesity is associated with low-grade inflammation and metabolic disorders, clinical studies suggested some obese people were metabolically healthy with smaller adipocyte size compared with metabolically abnormal obese (MAO). This indicated adipocyte size may be an important predictor underlay the distinction between MAO and metabolically healthy obese. As recent study has shown that adipocytes expressed class II major histocompatibility complex (MHCII), which functioned as APCs during obesity. However, the relationship between adipocyte hypertrophy and MHCII expression was not involved. Here we hypothesize that hypertrophic adipocytes could be associated with upregulating MHCII to influence adipose tissue metabolism.MethodsAdipocytes were sorted by fluorescence-activated cell sorting (FACS) according to the cell size from MAO mice. The activation of MHCII, T cells and related signaling molecules were examined by FACS, ELISA and western blotting. 3T3-L1 cell line and primary adipocytes were used to examine the effect of free fatty acids (FFA) on adipocytes enlargement and MHCII expression.ResultsMAO mice had a significant increase in adipocytes size and FFA concentration. The large adipocytes from both obese and non-obese mice expressed higher levels of MHCII than small adipocytes. Importantly, large adipocytes from obese mice stimulated CD4(+) T cells to secrete more interferon (IFN)-γ. Furthermore, the activation of the JNK-STAT1 pathway was involved in upregulation of MHCII in large adipocytes. In vitro FFA treatment promoted adipocyte hypertrophy and expression of MHCII-associated genes.ConclusionsThis study demonstrates that large adipocytes highly express MHCII and function as APC to stimulate IFN-γ-expressing CD4(+) T cells, in which FFA may have important roles before IFN-γ elevated. These findings suggest that adipocyte hypertrophy, rather than overall obesity, is the major contributor to adipose tissue inflammation and insulin resistance.

Project description:BackgroundBivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA).MethodsWe performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored.ResultsWe identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells.ConclusionsBvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity.

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MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4⁺ T cells in vivo.

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MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4<sup>+</sup> T cells in vivo.

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