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Monomeric agonist peptide/MHCII complexes activate T-cells in an autonomous fashion.

ABSTRACT: Molecular crowding of agonist peptide/MHC class II complexes (pMHCIIs) with structurally similar, yet per se non-stimulatory endogenous pMHCIIs is postulated to sensitize T-cells for the recognition of single antigens on the surface of dendritic cells and B-cells. When testing this premise with the use of advanced live cell microscopy, we observe pMHCIIs as monomeric, randomly distributed entities diffusing rapidly after entering the APC surface. Synaptic TCR engagement of highly abundant endogenous pMHCIIs is low or non-existent and affects neither TCR engagement of rare agonist pMHCII in early and advanced synapses nor agonist-induced TCR-proximal signaling. Our findings highlight the capacity of single freely diffusing agonist pMHCIIs to elicit the full T-cell response in an autonomous and peptide-specific fashion with consequences for adaptive immunity and immunotherapeutic approaches.

SUBMITTER: Platzer R

PROVIDER: S-EPMC10626418 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Monomeric agonist peptide/MHCII complexes activate T-cells in an autonomous fashion.

Platzer René R Hellmeier Joschka J Göhring Janett J Perez Iago Doel ID Schatzlmaier Philipp P Bodner Clara C Focke-Tejkl Margarete M Schütz Gerhard J GJ Sevcsik Eva E Stockinger Hannes H Brameshuber Mario M Huppa Johannes B JB

EMBO reports 20230928 11

Molecular crowding of agonist peptide/MHC class II complexes (pMHCIIs) with structurally similar, yet per se non-stimulatory endogenous pMHCIIs is postulated to sensitize T-cells for the recognition of single antigens on the surface of dendritic cells and B-cells. When testing this premise with the use of advanced live cell microscopy, we observe pMHCIIs as monomeric, randomly distributed entities diffusing rapidly after entering the APC surface. Synaptic TCR engagement of highly abundant endoge ...[more]

PMID: 37768718

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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.

Dataset Information

Monomeric agonist peptide/MHCII complexes activate T-cells in an autonomous fashion.

Publications

Monomeric agonist peptide/MHCII complexes activate T-cells in an autonomous fashion.

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