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.

The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-β are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown. Here we have examined the role of natural and adaptive regulatory T cells in the control of malaria infection and find that classical CD4+CD25hi (and Foxp3+) regulatory T cells do not significantly influence the outcome of infections with the lethal (17XL) strain of Plasmodium yoelii (PyL). In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25−, Foxp3−, and CD127− and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance. In summary, we have identified a population of induced Foxp3− regulatory (Tr1) T cells, characterised by production of IL-10 and down regulation of IL-7Rα, that modulates the inflammatory response to malaria.

It is well established that IFN-γ is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. To date, however, the temporal and tissue-specific cellular sources of IFN-γ during P. berghei ANKA infection have not been investigated and it is not known if IFN-γ production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-γ reporter mice, we show that NK cells dominate the IFN-γ response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4+ and CD8+ T cells. Importantly, we demonstrate that IFN-γ producing CD4+ T cells, but not innate or CD8+ T cells, can promote the development of ECM in normally resistant IFN-γ−/− mice infected with P. berghei ANKA. Adoptively transferred wild-type (WT) CD4+ T cells accumulate within the spleen, lung and brain of IFN-γ−/− mice and induce ECM through active IFN-γ secretion, which increases accumulation of endogenous IFN-γ−/− CD8+ T cells within the brain. Depletion of endogenous IFN-γ−/− CD8+ T cells abrogated the ability of WT CD4+ T cells to promote ECM. Finally we show that IFN-γ production specifically by CD4+ T cells is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8+ T cell accumulation. These observations demonstrate, for the first time, the importance of and pathways by which IFN-γ-producing CD4+ T cells promote the development of ECM during P. berghei ANKA infection.

Investigation of the role of regulatory T cells (Treg) in model systems is facilitated by their depletion using anti-CD25 antibodies, but there has been considerable debate about the effectiveness of this strategy. Here, we have compared the depletion and repopulation of CD4+CD25+Foxp3+ Treg in uninfected and malaria-infected mice using 7D4 and/or PC61 anti-CD25 antibodies. We find that numbers and percentages of CD25hi cells, but not Foxp3+ cells, are transiently reduced after 7D4 treatment whereas treatment with PC61 - alone or in combination with 7D4 (7D4+PC61) - reduces, but does not eliminate, Foxp3+ cells for up to two weeks. Importantly, all protocols fail to eliminate significant populations of CD25-Foxp3+ or CD25lowFoxp3+ cells, which retain potent regulatory capacity. By adoptive transfer we show that repopulation of the spleen by CD25hiFoxp3+ cells results from re-expression of CD25 on peripheral populations of CD25-Foxp3+ but not from conversion of peripheral Foxp3- cells. CD25hiFoxp3+ repopulation occurs more rapidly in 7D4-treated mice than in 7D4+PC61-treated mice, reflecting ongoing clearance of emergent CD25+Foxp3+ cells by persistent PC61 antibody. However, in 7D4+PC61-treated mice undergoing acute malaria infection, repopulation of the spleen by CD25+Foxp3+ cells occurs extremely rapidly, with malaria infection driving proliferation and CD25 expression in peripheral CD4+CD25-Foxp3+ cells and/or conversion of CD4+CD25-Foxp3- cells. Finally, we reveal an essential role for IL-2 for re-expression of CD25 by Foxp3+ cells after anti-CD25 treatment and observe that TGF-β is required - in the absence of CD25 and IL-2 - to maintain splenic Foxp3+ cell numbers and a normal ratio of Treg:non-Treg cells.

In most models of blood-stage malaria infection, proinflammatory immune responses are required for control of infection and elimination of parasites. We hypothesized therefore that the fulminant infections caused in mice by the lethal strain of Plasmodium yoelii (17XL) might be due to failure to activate a sufficient inflammatory response. Here we have compared the adaptive CD4 ؉ T-cell and innate immune response to P. yoelii 17XL with that induced by the self-resolving, nonlethal strain of P. yoelii, 17X(NL). During the first 7 to 9 days of infection, splenic effector CD4 ؉ T-cell responses were similar in mice with lethal and nonlethal infections with similar levels of activation in vivo and equivalent proliferation in vitro following mitogenic stimulation. Nonspecific T-cell hyporesponsiveness was observed at similar levels during both infections and was due, in part, to suppression mediated by CD11b ؉ cells. Importantly, however, RAG ؊/؊ mice were able to control the initial growth phase of nonlethal P. yoelii infection as effectively as wild-type mice, indicating that T cells and/or B cells play little, if any, role in control of the primary peak of parasitemia. Somewhat unexpectedly, we could find no clear role for either NK cells or gamma interferon (IFN-␥) in controlling primary P. yoelii infection. In contrast, depletion of monocytes/macrophages exacerbated parasite growth and anemia during both lethal and nonlethal acute P. yoelii infections, indicating that there is an IFN-␥-, NK cell-, and T-cell-independent pathway for induction of effector macrophages during acute malaria infection.