Although several subsets of intestinal antigen presenting cells (APCs) have been described, to date is no systematic evaluation of their phenotypes, functions and geographical localization. Here we used 10-color flow cytometry, to define the major APC subsets in the small and large intestine LP. LP APCs could be subdivided into CD11c+CD11b−, CD11c+CD11b+, and CD11cdullCD11b+ subsets. CD11c+CD11b− cells were largely CD103+F4/80− DCs, while the CD11c+CD11b+ subset comprised of CD11c+CD11b+CD103+F4/80− DCs versus CD11c+CD11b+CD103-F4/80+ macrophage-like cells. The majority of CD11cdullCD11b+ cells were CD103-F4/80+ macrophages. Although macrophages were more efficient at inducing Foxp3+ Treg cells than DCs, at higher ratios of T:APC cells all DC subsets efficiently induced Foxp3+ Treg cells. In contrast, only CD11c+CD11b+CD103+ DCs efficiently induced TH-17 cells. Consistent with this, the geographical distribution of CD11c+CD11b+CD103+ DCs correlated with that of TH-17 cells, with duodenum>jejunum>ileum>colon. Conversely, CD11c+CD11b−CD103+ DCs, macrophages and Foxp3+ Treg cells were most abundant in the colon and scarce in the duodenum. Importantly however, the ability of DC and macrophage subsets to induce Foxp3+ Tregs versus TH17 cells was strikingly dependent on the source of the mouse strain. Thus, DCs from C57BL/6 mice from Charles River, (that have segmented filamentous bacteria, which induce robust levels of TH-17 cells in situ (1, 2)), were more efficient at inducing TH-17 cells, and less efficient at inducing FoxP3+ Treg cells than DCs from B6 mice from Jackson Laboratories. Thus the functional specializations of APC subsets in the intestine is dependent on the T:APC ratios, regional localization, and the source of the mouse strain.
Summary Resolution of acute and chronic viral infections requires activation of innate cells to initiate and maintain adaptive immune responses. Here we report that infection with acute Armstrong (ARM) or chronic Clone 13 (C13) strains of lymphocytic choriomeningitis virus (LCMV) led to two distinct phases of innate immune response. During the first 72hr of infection, dendritic cells upregulated activation markers, and stimulated anti-viral CD8+ T cells, independent of viral strain. Seven days after infection, there was an increase in Ly6Chi monocytic and Gr-1hi neutrophilic cells in lymphoid organs and blood. This expansion in cell numbers was enhanced and sustained in C13 infection, whereas it occurred only transiently with ARM infection. These cells resembled myeloid-derived suppressor cells, and potently suppressed T cell proliferation. The reduction of monocytic cells in Ccr2−/− mice or after Gr-1 antibody depletion enhanced anti-viral T cell function. Thus, innate cells have an important immunomodulatory role throughout chronic infection.
Mycobacterium tuberculosis causes chronic infection of mononuclear phagocytes, especially resident (alveolar) macrophages, recruited macrophages, and dendritic cells. Despite the importance of these cells in tuberculosis (TB) pathogenesis and immunity, little is known about the population dynamics of these cells at the sites of infection. We used a combination of congenic monocyte adoptive transfer, and pulse-chase labeling of DNA, to determine the kinetics and characteristics of trafficking, differentiation, and infection of mononuclear phagocytes during the chronic, adaptive immune phase of M. tuberculosis infection in mice. We found that Ly6Chi monocytes traffic rapidly to the lungs, where a subpopulation become Ly6Clo and remain in the lung vascular space, while the remainder migrate into the lung parenchyma and differentiate into Ly6Chi dendritic cells, CD11b+ dendritic cells, and recruited macrophages. As in humans with TB, M. tuberculosis-infected mice have increased numbers of blood monocytes; this is due to increased egress from the bone marrow, and not delayed egress from the blood. Pulse-chase labeling of dividing cells and flow cytometry analysis revealed a T1/2 of ~15 hrs for Ly6Chi monocytes, indicating that they differentiate rapidly upon entry to the parenchyma of infected lungs; in contrast, cells that differentiate from Ly6Chi monocytes turn over more slowly, but diminish in frequency in less than one week. New cells (identified by pulse-chase labeling) acquire bacteria within 1–3 days of appearance in the lungs, indicating that bacteria regularly encounter new cellular niches, even during the chronic stage of infection. Our findings that mononuclear phagocyte populations at the site of M. tuberculosis infection are highly dynamic provide support for specific approaches for host-directed therapies directed at monocytes, including trained immunity, as potential interventions in TB, by replacing cells with limited antimycobacterial capabilities with newly-recruited cells better able to restrict and kill M. tuberculosis.
Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics “emergency hematopoiesis,” a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.
Further studies revealed that CD4 T cells in lung lesions are distant from the infected cells, suggesting that, even if they can be activated, the positioning of CD4 T cells and their direct interactions with infected cells may be limiting determinants of immunity in tuberculosis.
Mycobacterium tuberculosis causes chronic infection of mononuclear phagocytes, especially resident (alveolar) macrophages, recruited macrophages, and dendritic cells. Despite the importance of these cells in tuberculosis (TB) pathogenesis and immunity, little is known about the population dynamics of these cells at the sites of infection. We used a combination of congenic monocyte adoptive transfer, and pulse-chase labeling of DNA, to determine the kinetics and characteristics of trafficking, differentiation, and infection of mononuclear phagocytes during the chronic, adaptive immune phase of M. tuberculosis infection in mice.We found that Ly6C hi monocytes traffic rapidly to the lungs, where a subpopulation become Ly6C lo and remain in the lung vascular space, while the remainder migrate into the lung parenchyma and differentiate into Ly6C hi dendritic cells, CD11b + dendritic cells, and recruited macrophages. As in humans with TB, M. tuberculosis-infected mice have increased numbers of blood monocytes; this is due to increased egress from the bone marrow, and not delayed egress from the blood. Pulse-chase labeling of dividing cells and flow cytometry analysis revealed a T 1/2 of ~15 hrs for Ly6C hi monocytes, indicating that they differentiate rapidly upon entry to the parenchyma of infected lungs; in contrast, cells that differentiate from Ly6C hi monocytes turn over more slowly, but diminish in frequency in less than one week. New cells (identified by pulse-chase labeling) acquire bacteria within 1-3 days of appearance in the lungs, indicating that bacteria regularly encounter new cellular niches, even during the chronic stage of infection. Our findings that mononuclear phagocyte populations at the site of M. tuberculosis infection are highly dynamic provide support for specific approaches for host-directed therapies directed at monocytes, including trained immunity, as potential interventions in TB, by replacing cells with limited antimycobacterial capabilities with newly-recruited cells better able to restrict and kill M. tuberculosis.
Mucosal immunity is influenced in large part by the dynamic interplay between various intestinal antigen‐presenting cell subsets and T lymphocytes. Using 10‐color flow cytometry, we have defined the major DC and macrophage subsets in the small and large intestine LP as distinguishable by the reciprocal expression of CD103 and F4/80, respectively, and not exclusively by CD11b or CD11c. Intestinal F4/80+ macrophages expressed IL‐10, TGF‐β, retinoic acid‐generating enzymes and promoted the differentiation of inducible FoxP3+ regulatory T cells. Alternatively, CD11b+, but not CD11b−, CD103+ LP DCs expressed IL‐6 and TGF‐β as well as retinoic acid‐generating enzymes and efficiently induced the differentiation of TH‐17 cells. These CD103+ LP DC subsets displayed striking region‐specific localization along the intestine with CD11b−CD103+ LP DCs appearing most abundantly in the large intestine while CD11b+CD103+ LP DCs were most prevalent in the upper small intestine. The distribution pattern of CD11b+CD103+ LP DCs in particular correlated with the representation of TH‐17 cells in the intestine and during intestinal inflammation CD11b+CD103+ LP DCs accumulated in the colonic LP as did TH‐17 cells. Our results suggest that CD11b+CD103+ LP DCs may be targets for modulating IL‐17 producing T cell responses during intestinal inflammation.
Mucosal immunity is influenced in large part by the dynamic interplay between various intestinal antigen‐presenting cell subsets and T lymphocytes. Using 10‐color flow cytometry, we have defined the major DC and macrophage subsets in the small and large intestine LP as distinguishable by the reciprocal expression of CD103 and F4/80, respectively, and not exclusively by CD11b or CD11c. Intestinal F4/80+ macrophages expressed IL‐10, TGF‐β, retinoic acid‐generating enzymes and promoted the differentiation of inducible FoxP3+ regulatory T cells. Alternatively, CD11b+, but not CD11b−, CD103+ LP DCs expressed IL‐6 and TGF‐β as well as retinoic acid‐generating enzymes and efficiently induced the differentiation of TH‐17 cells. These CD103+ LP DC subsets displayed striking region‐specific localization along the intestine with CD11b−CD103+ LP DCs appearing most abundantly in the large intestine while CD11b+CD103+ LP DCs were most prevalent in the upper small intestine. The distribution pattern of CD11b+CD103+ LP DCs in particular correlated with the representation of TH‐17 cells in the intestine and during intestinal inflammation CD11b+CD103+ LP DCs accumulated in the colonic LP as did TH‐17 cells. Our results suggest that CD11b+CD103+ LP DCs may be targets for modulating IL‐17 producing T cell responses during intestinal inflammation.
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