Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

IL-10 is an anti-inflammatory cytokine. During infection it inhibits the activity of Th1 cells, NK cells, and macrophages, all of which are required for optimal pathogen clearance but also contribute to tissue damage. In consequence, IL-10 can both impede pathogen clearance and ameliorate immunopathology. Many different types of cells can produce IL-10, with the major source of IL-10 varying in different tissues or during acute or chronic stages of the same infection. The priming of these various IL-10-producing populations during infections is not well understood and it is not clear whether the cellular source of IL-10 during infection dictates its cellular target and thus its outcome. In this article we review the biology of IL-10, its cellular sources, and its role in viral, bacterial, and protozoal infections.

IL-10: The Master Regulator of Immunity to Infection

Visceral leishmaniasis (VL) is a systemic protozoan disease that is transmitted by phlebotomine sandflies. Poor and neglected populations in East Africa and the Indian sub-continent are particularly affected. Early and accurate diagnosis and treatment remain key components of VL control. In addition to improved diagnostic tests, accurate and simple tests are needed to identify treatment failures. Miltefosine, paromomycin and liposomal amphotericin B are gradually replacing pentavalent antimonials and conventional amphotericin B as the preferred treatments in some regions, but in other areas these drugs are still being evaluated in both mono- and combination therapies. New diagnostic tools and new treatment strategies will only have an impact if they are made widely available to patients.

http://www.bio.umass.edu/micro/klingbeil/590s/Reading/Leishdiag2007.pdf

Visceral leishmaniasis: what are the needs for diagnosis, treatment and control?

Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis Dysregulation of IL-10 is associated with enhanced immunopathology in response to infection as well as increased risk for development of many autoimmune diseases Thus a fundamental understanding of IL-10 gene expression is critical for our comprehension of disease progression and resolution of host inflammatory response In this review, we discuss modes of regulation of IL-10 gene expression in immune effector cell types, including signal transduction, epigenetics, promoter architecture, and post-transcriptional regulation, and how aberrant regulation contributes to immunopathology and disease progression

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Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease

T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-gamma, and lymphotoxin-alpha and stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.

Type 1/Type 2 Immunity in Infectious Diseases

We have found that an important Th2 cytokine, IL-10, is produced by tissues from patients acutely infected with Leishmania donovani. In all individuals tested, IL-10 mRNA production was increased in lymph nodes taken during acute disease over that observed in postacute samples. In contrast, both pre- and posttreatment lymph nodes had readily detected mRNA for IFN-gamma and IL-2. A down-regulating effect of IL-10 on leishmania-induced proliferative responses was demonstrated when Hu rIL-10 was added to cultures of PBMC from clinically cured individuals. PBMC from individuals with acute visceral leishmaniasis responded to stimulation with leishmania lysate by producing IL-10 mRNA. Simultaneously cultured PBMC collected from the same patients after successful chemotherapy produced no detectable IL-10 mRNA after leishmania antigen stimulation. Neutralizing anti-IL-10 mAb added to PBMC from patients with acute visceral leishmaniasis markedly increased the proliferative response to leishmania lysate. Finally, we observed mRNA for IL-10 and IFN-gamma concurrently in a lesion from a patient with post-kala-azar dermal leishmaniasis (PKDL). These results indicate the production of IL-10 during L. donovani infection, and suggest a role for this cytokine in the regulation of immune responsiveness during visceral leishmaniasis.

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Interleukin 10 production correlates with pathology in human Leishmania donovani infections.

IL-10 has been shown to inhibit some aspects of macrophage activation, including the in vitro IFN-gamma-mediated intracellular killing of the protozoan parasite Trypanosoma cruzi. We have previously shown that genetically susceptible mice produced more IL-10 during T. cruzi infection than resistant mice, suggesting an association between IL-10 production and disease susceptibility. In the present study, such an association was documented. IL-10 mRNA was present in the spleens of susceptible C57BL/6 mice, but not in resistant (C57BL/6 x DBA/2) F1 mice, as early as 2 days after infection with T. cruzi. In susceptible mice, IL-10 mRNA was found in enriched populations of splenic T cells and peritoneal macrophages by 4 days after infection. By 14 days after infection, IL-10 mRNA was detected in enriched populations of splenic T cells and peritoneal macrophages, as well as by splenic B cells and macrophages. In SCID mice infected with T. cruzi, IL-10 mRNA was detected in peritoneal cells 2 days after infection. The IL-10 mRNA production was not abolished by treatment with anti-asialo GM-1 Ab before infection, which is consistent with its production by macrophages. Finally, the role of endogenous IL-10 production in the susceptibility to T. cruzi infection was demonstrated by the protection of highly susceptible C57BL/6 mice against acute disease and death from T. cruzi by the administration of neutralizing anti-IL-10 mAb. This study demonstrated an important and perhaps essential role of IL-10 in mediating in vivo susceptibility to T. cruzi infection.

IL-10 mediates susceptibility to Trypanosoma cruzi infection.

gp63, an abundant and conserved leishmania cell surface protein, has been implicated in the ability of these parasitic protozoa to infect macrophages in vitro and has shown potential as a protective immunogen in mice. However, little is known regarding human immune responses to this glycoprotein Ag. In this study, human T lymphocyte responses to Leishmania amazonensis native gp63 and to recombinant gp63 (rgp63) produced in Escherichia coli were evaluated in individuals with active or cured cutaneous, mucosal or visceral leishmaniasis. Both native and rgp63 elicited strong proliferative responses in all patients tested. In addition, IFN-gamma was produced in response to stimulation with both forms of the protein. T cell lines generated from PBMC by stimulation with native or rgp63 were phenotypically similar, and proliferated and produced IFN-gamma in response to stimulation with both forms of the molecule. These results suggest that gp63 is a strong T cell immunogen and that the recombinant and native forms can elicit the same type of T cell response from infected patients. In order to compare the immunogenic properties of these two forms of gp63, PBMC from naive (uninfected) donors were sensitized in vitro with native or rgp63. T cell lines generated against rgp63 proliferated in response to rgp63, but failed to proliferate in response to native gp63 or to promastigote lysate. Thus, rgp63 was effective in eliciting T cell responses from patients with active or cured leishmania infection, but did not effectively induce T cell responses under the conditions used.

Human T cell responses to gp63, a surface antigen of Leishmania.

Lipophosphoglycan (LPG) is a glycoconjugate present on the surface of Leishmania promastigotes that has been reported to promote intracellular survival of these parasites, to protect mice against leishmaniasis, and to elicit T cell responses in infected mice and humans. We investigated whether LPG and its components could elicit proliferative responses and cytokine secretion from leishmaniasis patient PBMC. LPG prepared by standard methods (LPG-1) stimulated patients T cells to proliferate and secrete IFN-gamma. LPG was fractionated into several components. An LPG-1-specific T cell line was shown to respond to the core region but not to the repeating saccharide units. LPG-1 was fractionated to yield an LPG-free- associated protein complex and an LPG-2 fraction that was more than 95% depleted of associated protein. The ability of LPG-2 to stimulate T cells was significantly decreased over that of LPG-1. In contrast, LPG-AP stimulated T cell proliferation and IFN-gamma production. Therefore, proteins associated with LPG were effective in eliciting patient T cell responses, whereas the glycolipid enriched moiety was weakly effective or ineffective at stimulating these responses.

Stimulation of human T lymphocytes by Leishmania lipophosphoglycan-associated proteins.

The importance of Ag-specific gamma delta T lymphocytes in human immune responses to pathogenic organisms is unknown. In the present study the expression of gamma delta TCR on T lymphocytes from patients with cutaneous, mucosal, or visceral leishmaniasis was examined. All of these patient groups had elevated levels of gamma delta T cells in peripheral blood. Patients' gamma delta T cells included CD8+ as well as null cells. The percentage of T cells expressing gamma delta TCR was increased significantly by stimulation in vitro with certain parasite Ag. T-cell lines generated by stimulation with promastigote lysates of Leishmania amazonensis or L. braziliensis typically contained 25 to 60% gamma delta T cells. In contrast, two immunodominant surface Ag of L. amazonensis, gp63 and gp42, did not expand gamma delta T cells from infected patients, although both Ag elicited strong alpha beta T-cell responses. gamma delta T cells isolated from a Leishmania-specific T-cell line responded to stimulation with promastigote lysate. Of particular interest, gamma delta T cells from PBMC of a patient with mucosal leishmaniasis responded to stimulation with a recombinant 70 kDa heat shock protein of L. chagasi. This study demonstrated that several clinical forms of leishmaniasis induced elevated numbers of gamma delta T cells that responded specifically to Leishmania Ag in vitro. Therefore, this component of the T-cell response to Leishmania may impact the outcome of clinical disease.

D M Russo

Papers

Interleukin 10 production correlates with pathology in human Leishmania donovani infections.

IL-10 mediates susceptibility to Trypanosoma cruzi infection.

Human T cell responses to gp63, a surface antigen of Leishmania.

Stimulation of human T lymphocytes by Leishmania lipophosphoglycan-associated proteins.

Antigen-reactive gamma delta T cells in human leishmaniasis.