Intestinal monocytes and macrophages are required for T cell polarization in response to <i>Citrobacter rodentium</i>

“…Indeed, intestinal macrophages orchestrate differential T cell immunity, depending on the bacterial antigen, with T H 17 cells, T H 1 cells, or regulatory T cells (T reg cells) capable of being differentially induced (16)(17)(18)(19). Macrophages further exhibit heterogeneity by anatomic location (20).…”

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confidence: 99%

Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques

Ortiz

DiNapoli

Brenchley

2015

J Virol

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Macrophages regulate tissue immunity, orchestrating the initiation and resolution of antimicrobial immune responses and repair of damaged tissue architecture. Their dysfunction can, thus, manifest in either pro-and anti-inflammatory responses. Indeed, despite the importance of macrophage function in health and disease, the role of tissue-resident macrophages in human immunodeficiency virus (HIV) disease progression remains incompletely defined. Here, we use flow cytometry to assess the phenotypes and functions of macrophages isolated from the spleens, axillary lymph nodes, colons, jejuna, and livers of healthy and chronically simian immunodeficiency virus (SIV)-infected Asian macaques, the prominent nonhuman primate model for HIV infection. Our data demonstrate that macrophages from healthy animals exhibit considerable phenotypic and functional heterogeneity across tissues and across a variety of stimuli. Further, our analysis reveals changes in the lipopolysaccharide (LPS) responsiveness of macrophages isolated from SIV-infected animals. We anticipate that our findings will inform future research into macrophage-directed immunity across a variety of primate diseases. IMPORTANCE These findings highlight the functional and phenotypic heterogeneity of tissue macrophages in different anatomic sites and as a result of SIV infection. We believe that our data will lead to novel therapeutic interventions aimed at altering the proinflammatory capacity of tissue macrophages in progressively HIV-infected individuals.N onhuman primates (NHPs) serve as an ultimate model for studying some human diseases and development. NHPs share upwards of 90% genetic similarity to humans, exhibit a largely parallel developmental program, and mirror human anatomy and anatomic process (1). The zoonotic transmission of pathogens from NHPs to humans remains a significant concern and has been documented to include herpes simian B virus, Marburg virus, and simian immunodeficiency virus (SIV), the ancestral progenitor of human immunodeficiency virus (HIV). Despite the many evolutionarily conserved similarities between human and divergent NHP species, differences in disease outcome are apparent. Importantly, HIV type 1 (HIV-1) infection in humans and SIV infection in Asian macaques result in similar, severe disease progressions, while SIV infection in NHPs of African origin results in a nonpathogenic course of disease (2). Given the limited divergence exhibited between primate species, a complete dissection of immunological processes in NHP species will yield critical information regarding potential mechanisms of disease progression and remission in human patients.SIV infection in Asian macaques and HIV infection of humans are characterized by persistent immune activation that is attributable, in part, to damage to the gastrointestinal barrier and subsequent microbial translocation (3, 4). The gastrointestinal lumen is estimated to contain 10 14 commensal and potentially pathogenic microbes that are kept separate from the underlying tissu...

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“…Recently, intestinal monocytes and macrophages were found to be required for Th1 polarization of Th cells in response to C. rodentium (19), but the site where naive T cells are primed and initially polarized toward Th1 polarization after C. rodentium infection has hitherto not been addressed. In this study, we describe three small LNs in the mesenterium, which drain lymph selectively from the large intestine and identify them as the site in which DC and Th1 helper T cells are activated in response to C. rodentium infection.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings corroborate the existence of three distinct LNs draining the colon, but also identify a role for each one of these in draining the proximal, transverse, or descending section of the colon. We show that microbial challenge of the colon with Citrobacter rodentium infection leads to selective activation of especially pDC in these and identify unique pathogen-sensing and activation pathways in pDC with potential importance in mounting a protective Th1 response (19,20) to this effacing-attaching pathogen.…”

mentioning

confidence: 93%

Activation of Plasmacytoid Dendritic Cells in Colon-Draining Lymph Nodes during Citrobacter rodentium Infection Involves Pathogen-Sensing and Inflammatory Pathways Distinct from Conventional Dendritic Cells

Toivonen

Kong

Rasool

et al. 2016

The Journal of Immunology

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Dendritic cells (DCs) bear the main responsibility for initiation of adaptive immune responses necessary for antimicrobial immunity. In the small intestine, afferent lymphatics convey Ags and microbial signals to mesenteric lymph nodes (LNs) to induce adaptive immune responses against microbes and food Ags derived from the small intestine. Whether the large intestine is covered by the same lymphatic system or represents its own lymphoid compartment has not been studied until very recently. We identified three small mesenteric LNs, distinct from small intestinal LNs, which drain lymph specifically from the colon, and studied DC responses to the attaching and effacing pathogen Citrobacter rodentium in these. Transcriptional profiling of conventional (CD11chighCD103high) DC and plasmacytoid (plasmacytoid DC Ag-1highB220+CD11cint) DC (pDC) populations during steady-state conditions revealed activity of distinct sets of genes in these two DC subsets, both in small intestinal and colon-draining LNs. C. rodentium activated DC especially in colon-draining LNs, and gene expression changed in pDC more profoundly than in conventional DC. Among the genes most upregulated in pDC were C-type lectin receptor CLEC4E, IL-1Rs (IL-1R1 and -2), proinflammatory cytokines (IL-1a and IL-6), and TLR6. Our results indicate that colon immune surveillance is distinct from that of the small intestine in terms of draining LNs, and identify pDC as active sentinels of colonic inflammation and/or microbial dysbiosis.

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Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium

Abstract: Using a new mouse model, the specific deletion of monocytes and macrophages reveals that, although not required to initiate immunity to Citrobacter rodentium, they contribute to the adaptive response via IL-12 secretion to induced IFN-γ+ Th1 polarization.

Cited by 174 publications

References 92 publications

The transcription factor NR4A3 controls CD103+ dendritic cell migration

The transcription factor NR4A3 controls CD103+ dendritic cell migration

Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques

Activation of Plasmacytoid Dendritic Cells in Colon-Draining Lymph Nodes during Citrobacter rodentium Infection Involves Pathogen-Sensing and Inflammatory Pathways Distinct from Conventional Dendritic Cells

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