Biology subjects

Peters, N. C.

Publications and source records attributed to Peters, N. C..

4 recordsLinked to original sources

bioRxiv2026

Pre-existing Th1 immunity is abrogated by ongoing recruitment of monocytic host cells that are refractory to activation

Protective immunity against many infectious diseases develops following primary infection, called infection induced immunity (III), and provides a blueprint for vaccination. However, many vaccination strategies have failed. In the parasitic Leishmania major model of self-healing cutaneous disease, control of secondary challenge infection relies on pre-existing T helper (Th)1-dependent activation of skin-infiltrating monocytes for elimination of intracellular parasites. To better understand immune-evasion of pre-existing Th1 immunity by pathogens, we investigated the pathogen-niche established following non-healing challenge infection with the L. amazonensis parasite in a setting of pre-existing III. Following secondary challenge, pre-existing Th1 III initially controlled infection but ultimately failed. Loss of protection was not overtly STAT6- or IL-10-mediated. Rather, monocyte-lineage tracing revealed inflammatory monocyte-derived PD-L1+PD-L2+ macrophages provide an intracellular pathogen-niche and facilitate evasion of pre-existing Th1 immunity. Anti-PD-1 immune checkpoint blockade enhanced uninfected, but not infected, monocyte-derived cell activation and depletion of monocyte-derived precursors improved parasite control. These observations suggest that evasion of pre-existing Th1 immunity in this setting is not due to a failure of the Th1 response, but rather due to infected-cell intrinsic defects in activation.

immunology↗

bioRxiv2025

The pore-forming protein APOL7C ruptures Leishmania major-containing parasitophorous vacuoles in dendritic cells to promote IL-12 production and the induction of T helper type 1 immunity

Classical dendritic cells (cDCs) are required for the efficient priming of T helper type 1 (Th1) immunity against Leishmania major infections in mice. They do so by producing large quantities of IL-12 in response to L. major infection. IL-12 in turn supports the generation of protective CD4+ Th1 cells. However, the mechanism(s) by which L. major instigates robust IL-12 production by cDCs has not been addressed. Here we show that expression of a pore-forming protein called APOL7C is induced in cDCs by L. major infection. APOL7C is expressed in the cytosol of host cells and, remarkably, upon infection is recruited to L. major parasitophorous vacuoles (PVs) where it induces PV rupture. PV rupture leads to the exposure of L. major-derived pathogen-associated molecular patterns (PAMPs) to cytosolic pattern recognition receptors (PRRs). Cytosolic PRR signaling then drives IL-12 production by cDCs. Consequently, L. major challenge of APOL7C-deficient mice results in reduced numbers of IL-12 producing cDCs as well as a diminished Th1 response. In sum, our data indicate the presence of pore-forming proteins in the cytosol of cDCs that interfere with the intracellular niche of Leishmania to modulate immunity to these parasites.

cell biology↗

bioRxiv2025

Dysregulated lymphatic remodeling promotes immunopathology during non-healing cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a vector borne disease that is endemic to tropical and sub-tropical regions of the world disproportionately affecting those of low socioeconomic status. The combined role of the parasite and the hosts immune response in determining disease severity has made it challenging to discover new anti-leishmanial treatments. Previous work from our lab has established that the dermal lymphatic network is necessary for wound resolution in a model of healing CL with Leishmania major parasites. In CL, lymphatic remodeling allows for accumulated fluid to drain from the lesional site, thereby reducing disease severity. In this report, we present a new mechanism of immunopathology during non-healing CL brought about by L. amazonensis infection. We show non-healing CL develops alongside an accumulation of cells and fluid in the skin, resulting in chronic inflammation. Lymphatic remodeling is attenuated during the chronic phase of L. amazonensis infection. Moreover, the percentage of proliferating lymphatic endothelial cells (LECs) decreases from 6 to 12 weeks post infection (wpi), leading to a decrease over time in lymphatic vessel (LV) density. To induce lymphangiogenesis, exogenous vascular endothelial growth factor-C (VEGF-C) was administered by adenoviral delivery. VEGF-C increased LV dilation leading to reduced lesion sizes without altering parasite burdens, arguing targeting the lymphatics can alleviate immunopathology. Taken together, these results show impaired lymphatic function contributes to non-healing disease due to L. amazonensis infection and the lymphatics can be targeted to decrease inflammation in the skin during infection.

immunology↗

bioRxiv2023

The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells

Type I conventional dendritic cells (cDC1s) are essential for the generation of protective cytotoxic T lymphocyte (CTL) responses against many types of viruses and tumours. They do so by internalizing antigens from virally infected or tumour cells and presenting them to CD8+ T cells in a process known as cross-presentation (XP). Despite the obvious biological importance of XP, the molecular mechanism(s) driving this process remain unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein 7C (APOL7C) is upregulated in response to innate immune stimuli and is recruited to phagosomes. Strikingly, the association of APOL7C with phagosomes leads to phagosomal rupture, which in turn allows for the escape of engulfed protein antigens to the cytosol where they can be processed via the endogenous major histocompatibility complex (MHC) class I antigen processing pathway. We show that APOL7C recruitment to phagosomes is voltage-dependent and occurs in response to NADPH oxidase-induced depolarization of the phagosomal membrane. Our data indicate the presence of dedicated pore-forming apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDC1s to facilitate MHC class I presentation of exogenous antigen and to regulate adaptive immunity.

cell biology↗