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Mantegazza Research

Highlighted Publications

López Haber C.C., Levin-Konigsberg R., Karchin J., Zhu Y., Balla T., Grinstein S., Marks M.S. and Mantegazza A.R. 2020. “The lipid kinase Phosphatidylinositol-4-kinase IIα licenses phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells”. Proc. Natl. Acad. Sci. U.S.A. 117(45):28251-28262.

We show that the lipid kinase PI4K2a promotes phagosome autonomous signaling by ensuring the localization of TIRAP and TLR4 to PI4P-enriched platforms. Preserving phagosomal identity and autonomy is essential to differentiate between mild and potent immune responses depending on the encountered threat.

Mantegazza AR, Wynosky-Dolfi M, Casson C, Lefkovith A, Shin S, Brodsky I and Marks MS. 2017.“Increased autophagic sequestration in Adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity”. PLoS Pathogens 13(12): e1006785.

Our observations demonstrate a link between an endosomal trafficking adaptor (AP-3), the activity of the inflammasome and autophagy, and identify a novel regulator of inflammation. IL-1β and IL-17 deficiency may also explain neutropenia and recurrent bacterial infections in patients deficient in AP-3.

Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S and Marks MS. 2014. “TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation”. Proc. Natl. Acad. Sci. U.S.A. 111(43): 15508-15513.

We show that the compartmentalization of TLR signaling allows for an additional level of control of the antimicrobial immune response and optimizes MHC-II presentation of phagocytosed antigen to T cells by favoring the transfer of content between TLR signaling phagosomes, to boost and refine the immune response against pathogens.

Mantegazza AR, Guttentag SH, El-Benna J, Sasai M, Iwasaki A, Shen H, Laufer TM and Marks MS. 2012 “Adaptor Protein-3 in Dendritic Cells Facilitates Phagosomal Toll-like Receptor Signaling and Antigen Presentation to CD4(+) T Cells”. Immunity 36(5): 782-794. (Highlighted in: Nat Rev Immunol. 2012, 12(6): 400).

AP-3 is disabled in the genetic disorder Hermansky-Pudlak syndrome type 2 (HPS2), characterized by immunodeficiency. Our observations of an impaired immune response in the absence of AP-3 contributed to the understanding of HPS2 pathology.