Overlapping MHC class I/II Epitopes Program cDC1-like Differentiation of Monocyte-Derived Dendritic Cells via mTORC1 Signaling Inhibition

Amanya, S. B.; Murthy, A.; Bisht, N.; Bullock, Z. N.; Ernste, K. J.; Vazquez-Perez, J.; Liu, W.; Trivedi, A. J.; Oyewole-Said, D.; Paul, A.; Umokoro, L.; Akhanov, V.; Samuel, M.; Shi, Z.; Nguyen, M. H.; Jeong, M.; Iakova, P. A.; Jain, A.; Pham, K. T.; Kraushaar, D.; Konduri, V.; Decker, W. K.

doi:10.64898/2026.04.06.716309

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bioRxiv · 10.64898/2026.04.06.716309

Overlapping MHC class I/II Epitopes Program cDC1-like Differentiation of Monocyte-Derived Dendritic Cells via mTORC1 Signaling Inhibition

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Abstract

Viral infection polarizes monocyte-derived dendritic cells (moDC) to initiate type 1 immunity. The availability of overlapping (homologous) MHC class I and II epitopes, an occurrence frequently and primarily associated with intracellular infection, significantly enhances this process; however, the underlying mechanism(s) are unclear. We demonstrate that moDC loaded with homologous MHC epitopes acquire a cDC1-like phenotype in a process governed by mTORC1. mTORC1 pathway inhibition leads to NF-{kappa}B-mediated expression of IL-12 and other type I immune polarizing genes. The observed cDC1-like gene signature was also significantly enhanced in clinical moDC vaccine products made through methodologies that enforced class I and II antigenic homology. Collectively, these findings reveal a novel and previously unrecognized mechanism of immune governance that might also be exploited in cancer immunotherapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/716309v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@15475borg.highwire.dtl.DTLVardef@ffe5fborg.highwire.dtl.DTLVardef@53c761org.highwire.dtl.DTLVardef@46c4ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Amanya, S. B., Murthy, A., Bisht, N., Bullock, Z. N., Ernste, K. J., Vazquez-Perez, J., Liu, W., Trivedi, A. J., Oyewole-Said, D., Paul, A., Umokoro, L., Akhanov, V., Samuel, M., Shi, Z., Nguyen, M. H., Jeong, M., Iakova, P. A., Jain, A., Pham, K. T., Kraushaar, D., Konduri, V., Decker, W. K.. 2026-04-08. Overlapping MHC class I/II Epitopes Program cDC1-like Differentiation of Monocyte-Derived Dendritic Cells via mTORC1 Signaling Inhibition. https://doi.org/10.64898/2026.04.06.716309

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