Naturally occurring CD1c+ human regulatory dendritic cells: immunoregulators that are expanded in response to E. coli infection.
ABSTRACT Dendritic cells (DCs) play key roles in initiating and regulating immunity by sensing and integrating signals from a wide range of pathogens and dangers. Although much knowledge has been gained about the origins, phenotypes, and functions of mouse DC subsets, the challenge now is to translate this knowledge to the human immune system and reveal relevant biological significance in human health and disease. Considerably less is known about the phenotype and function of human DC subsets due to their rarity, the lack of distinctive markers, and limited access to human tissues. Initial studies of DCs in human blood revealed that steady-state myeloid DCs are comprised of the CD141(+) and CD1c(+) DC subsets as the equivalents to the mouse lymphoid resident CD8(+) and CD8(-) DC subsets, respectively. A new report in this issue of the European Journal of Immunology [Eur. J. Immunol. 2012. 42: 1512-1522] shows that human CD1c(+) myeloid DCs secrete IL-10 and display an immunoregulatory phenotype and function in response to Escherichia coli (E. coli). This finding adds a new element to the current understanding of human CD1c(+) DCs and reveals marked differences in human DC subsets during inflammation and microbial infection, as discussed in this Commentary.
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ABSTRACT: Dendritic cells (DCs) play a key role in critical illness and are depleted in spleens from septic patients and mice. To date, few studies have characterized the systemic effect of sepsis on DC populations in lymphoid tissues. We analyzed the phenotype of DCs and Th cells present in the local (mesenteric) and distant (inguinal and popliteal) lymph nodes of mice with induced polymicrobial sepsis (cecal ligation and puncture). Flow cytometry and immunohistochemical staining demonstrated that there was a significant local (mesenteric nodes) and partial systemic (inguinal, but not popliteal nodes) loss of DCs from lymph nodes in septic mice, and that this process was associated with increased apoptosis. This sepsis-induced loss of DCs occurred after CD3(+)CD4(+) T cell activation and loss in the lymph nodes, and the loss of DCs was not preceded by any sustained increase in their maturation status. In addition, there was no preferential loss of either mature/activated (MHCII(high)/CD86(high)) or immature (MHCII(low)/CD86(low)) DCs during sepsis. However, there was a preferential loss of CD8(+) DCs in the local and distant lymph nodes. The loss of DCs in lymphoid tissue, particularly CD8(+) lymphoid-derived DCs, may contribute to the alterations in acquired immune status that frequently accompany sepsis.The Journal of Immunology 10/2004; 173(5):3035-43. · 5.52 Impact Factor
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ABSTRACT: Human blood myeloid DCs can be subdivided into CD1c (BDCA-1)(+) and CD141 (BDCA-3)(+) subsets that display unique gene expression profiles, suggesting specialized functions. CD1c(+) DCs express TLR4 while CD141(+) DCs do not, thus predicting that these two subsets have differential capacities to respond to Escherichia coli. We isolated highly purified CD1c(+) and CD141(+) DCs and compared them to in vitro generated monocyte-derived DCs (MoDCs) following stimulation with whole E. coli. As expected, MoDCs produced high levels of the proinflammatory cytokines TNF, IL-6, and IL-12, were potent inducers of Th1 responses, and processed E. coli-derived Ag. In contrast, CD1c(+) DCs produced only low levels of TNF, IL-6, and IL-12 and instead produced high levels of the anti-inflammatory cytokine IL-10 and regulatory molecules IDO and soluble CD25. Moreover, E. coli-activated CD1c(+) DCs suppressed T-cell proliferation in an IL-10-dependent manner. Contrary to their mouse CD8(+) DC counterparts, human CD141(+) DCs did not phagocytose or process E. coli-derived Ag and failed to secrete cytokines in response to E. coli. These data demonstrate substantial differences in the nature of the response of human blood DC subsets to E. coli.European Journal of Immunology 06/2012; 42(6):1512-22. · 4.97 Impact Factor
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ABSTRACT: The effective vaccines developed against a variety of infectious agents, including polio, measles, and hepatitis B, represent major achievements in medicine. These vaccines, usually composed of microbial antigens, are often associated with an adjuvant that activates dendritic cells (DCs). Many infectious diseases are still in need of an effective vaccine including HIV, malaria, hepatitis C, and tuberculosis. In some cases, the induction of cellular rather than humoral responses may be more important because the goal is to control and eliminate the existing infection rather than to prevent it. Our increased understanding of the mechanisms of antigen presentation, particularly with the description of DC subsets with distinct functions, as well as their plasticity in responding to extrinsic signals, represent opportunities to develop novel vaccines. In addition, we foresee that this increased knowledge will permit us to design vaccines that will reprogram the immune system to intervene therapeutically in cancer, allergy, and autoimmunity.Immunity 10/2010; 33(4):464-78. · 19.80 Impact Factor