Filarial Antigens Impair the Function of Human Dendritic Cells during Differentiation

105

Both T cells and APC have been strongly implicated in the immune suppression observed during filarial nematode infections, but their relative roles are poorly understood, particularly in regard to timing and locality of action. Using Litomosoides sigmodontis infection of susceptible BALB/c mice, we have studied the progression of filarial immunosuppression leading to patent infection with blood microfilaremia. Patent infection is associated with decreased immune responsiveness in the draining thoracic lymph nodes (tLN) and intrinsically hyporesponsive CD4+ T cells at the infection site. We now show that we are able to separate, both in time and space, different suppressive mechanisms and cell populations that contribute to filarial hyporesponsiveness. L. sigmodontis infection recruited a F4/80+ population of alternatively activated macrophages that potently inhibited Ag-specific CD4+ T cell proliferative responses even in the presence of competent naive APC. T cell responsiveness was partially restored by neutralizing TGF-β, but not by blocking IL-10 or CTLA-4 signaling. During prepatent infection, the macrophage population was restricted to the infection site. However, once infection became patent with systemic release of microfilariae, the suppressive macrophage activity extended peripherally into the tLN. In contrast, the hyporesponsive CD4+ T cell phenotype remained localized at the infection site, and the tLN CD4+ T cell population recovered full Ag responsiveness in the absence of suppressive macrophages. Filarial immunosuppression, therefore, evolves over time at sites increasingly distal to infection, and the mechanisms of filarial down-regulation are dependent on proximity to the infection site.

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confidence: 86%

Section: Discussionmentioning

confidence: 99%

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Taylor

Harris

Nair

et al. 2006

105

“…The mechanisms underlying T cell hyporesponsiveness vary from organism to organism, but factors such as regulatory cytokines (7), altered function of APC (8 -10), T cell apoptosis (11), inducible NO synthase (5,12), and pro-and anti-inflammatory cytokines have been implicated to be associated with this defect. We have previously shown that MF Ag impairs the production of IL-12 and IL-10 by dendritic cells (DC) (10). In W. bancrofti infection, it has been shown that PBMC from MF individuals produce large amounts of IL-10 spontaneously and in response to Ag in vitro (13).…”

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confidence: 99%

Brugia malayiMicrofilariae Induce Cell Death in Human Dendritic Cells, Inhibit Their Ability to Make IL-12 and IL-10, and Reduce Their Capacity to Activate CD4+ T Cells

Semnani

Liu

Sabzevari

et al. 2003

Self Cite

108

109

Parasite Ag-specific T cell unresponsiveness and diminished IFN-γ production are immunologic hallmarks of patent infection with lymph-dwelling filarial nematodes. Although this diminished responsiveness is directed primarily against the intravascular microfilarial (MF) parasite stage and mediated in part by reduced APC function, the mechanisms involved are not fully understood. In this report, we demonstrate that human dendritic cells (DC) exposed to live MF up-regulate both the cell surface and gene expression of CD54 (ICAM-1). Moreover, live MF result in a 3-fold increase in DC death compared with MF-unexposed DC, primarily due to apoptosis. Notably, microarray and real-time RT-PCR data indicate that live MF concurrently up-regulate mRNA expression of proinflammatory molecules such as IL-8, RANTES, IL-1α, TNF-α, and IL-β in DC, the presence of which is also detected at the protein level, while inhibiting the production of IL-12 (p40 and p70) and IL-10. Soluble excretory-secretory products from live MF diminished IL-12 and IL-10 production and induced DC death, although to a lesser degree. Moreover, exposure of DC to live MF resulted in a decrease in the ability of DC to promote CD4+ T cell production of IFN-γ and IL-5. Our findings clearly suggest that the interaction between live MF and DC is complex but contributes to the hyporesponsiveness and parasite persistence associated with the MF+ state in the infected human. These data further suggest that MF induce an orchestrated response in APC that leads to a diminished capacity to function appropriately, which in turn has significant consequences for CD4+ T cells.

“…Previously, we used the bloodborne MF stage of Brugia malayi (Bm) (11,12) to study the interaction between this stage of the parasite and monocyte-derived DC, although this interaction occurs in the context of long-standing, chronic infection. We have shown that both MF Ag and live MF impair the function of monocyte-derived DC to produce IL-12 and IL-10 and to induce cytokines by CD4 ϩ T cells (11,12). Furthermore, using microarray analysis, we have shown that, whereas inflammatory responses in monocyte-derived macrophages were induced by live L3 of Bm, monocyte-derived DC were not affected by this parasite (13).…”

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confidence: 99%

Filaria-Induced Immune Evasion: Suppression by the Infective Stage of Brugia malayi at the Earliest Host-Parasite Interface

Semnani

Law

Kubofcik

et al. 2004

Self Cite

To assess the physiologic interactions between the infective stage of Brugia malayi—one of the extracellular parasites responsible for lymphatic filariasis in humans—and the APC with which they come in contact during their development and routes of travel, we have investigated the interaction between the infective stage (L3) of B. malayi and human Langerhans cells (LC) in the skin. Our data indicate that live L3 result in increased migration of LC from the epidermis without affecting the viability of these cells and up-regulation of the IL-18 cytokine involved in LC migration. Live L3 also result in down-regulation of MHC class I and II on the LC cell surface. Additionally, microarray data indicate that live L3 significantly down-regulated expression of IL-8 as well as of multiple genes involved in Ag presentation, reducing the capacity of LC to induce CD4+ T cells in allogeneic MLR, and thus resulting in a decreased ability of LC to promote CD4+ T cell proliferation and production of IFN-γ and IL-10. These data suggest that L3 exert a down-regulatory response in epidermal LC that leads to a diminished capacity of these cells to activate CD4+ T cells.