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bioRxiv · 10.1101/2024.08.21.609083

MLL1 directs gut-associated antibody responses to helminth and bacterial infections

Zhang, Y.·Chakma, C.·Kirn, A.·Zaini, A.·Farighi, R.·Xie, L.·Lopez-Urena, D.·Mileto, S.·Lyras, D.·Zaph, C.·Groom, J. R.·Good-Jacobson, K.
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Abstract

Soil-transmitted helminths are one of the most common infections globally, yet how to promote effective gut-associated humoral responses is not well understood. We identify the histone methyltransferase MLL1 as a key target to promote IgA-driven responses. Mll1 was increased in germinal center B cells in gut-associated lymphoid tissues, and Mll1-deficiency led to changes in the histone modification H3K4me3 on key B cell and immune-regulatory genes. Correspondingly, MLL1-deficient B cells had defective germinal centers and IgG1 in response to the helminth Trichuris muris. Yet, Mll1f/fCd23cre/+ mice expelled worms more rapidly compared to control mice. Accelerated worm clearance correlated with elevated IgA+ plasma cells, as well as both serum and fecal IgA. RNA-sequencing identified CCR9 as a key MLL1-regulated molecule. As such, Mll1f/fCd23cre/+ mice infected with T. muris had increased IgA+CCR9+ PC localized in the large intestine. Regulation of IgA by MLL1 was confirmed beyond T. muris infection. In vitro cultures confirmed Mll1-deficiency increased IgA+ plasma cells in a B cell-intrinsic manner, and IgA production was also increased in Mll1f/fCd23cre/+ mice infected with the bacterium C. rodentium. This study reveals MLL1 as a key target to promote IgA responses to gut-associated infections.

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Zhang, Y., Chakma, C., Kirn, A., Zaini, A., Farighi, R., Xie, L., Lopez-Urena, D., Mileto, S., Lyras, D., Zaph, C., Groom, J. R., Good-Jacobson, K.. 2024-08-22. MLL1 directs gut-associated antibody responses to helminth and bacterial infections. https://doi.org/10.1101/2024.08.21.609083

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