IL-17A–Producing γδ T Cells Suppress Early Control of Parasite Growth by Monocytes in the Liver

Abstract

Intracellular infections, such as those caused by the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL), require a potent host proinflammatory response for control. IL-17 has emerged as an important proinflammatory cytokine required for limiting growth of both extracellular and intracellular pathogens. However, there are conflicting reports on the exact roles for IL-17 during parasitic infections and limited knowledge about cellular sources and the immune pathways it modulates. We examined the role of IL-17 in an experimental model of VL caused by infection of C57BL/6 mice with L. donovani and identified an early suppressive role for IL-17 in the liver that limited control of parasite growth. IL-17–producing γδ T cells recruited to the liver in the first week of infection were the critical source of IL-17 in this model, and CCR2+ inflammatory monocytes were an important target for the suppressive effects of IL-17. Improved parasite control was independent of NO generation, but associated with maintenance of superoxide dismutase mRNA expression in the absence of IL-17 in the liver. Thus, we have identified a novel inhibitory function for IL-17 in parasitic infection, and our results demonstrate important interactions among γδ T cells, monocytes, and infected macrophages in the liver that can determine the outcome of parasitic infection.

Preferentially expanding Vγ1+ γδ T cells are associated with protective immunity against Plasmodium infection in mice

“…Malaria patients and Plasmodium ‐infected animals show increased γδ T cells in the peripheral blood and spleen . γδ T cells act as innate‐like lymphocytes and are involved with the host immune defence against various infections . Wild‐type (WT) mice can eliminate low virulent Plasmodium berghei XAT ( Pb XAT) parasites by 1 month after infection .…”

“…Vγ1 + and Vγ4 + γδ T cells (according to Heilig and Tonegawa nomenclature) are dominant subsets in murine spleen and have distinct functions in the host response against infection, immune cell homoeostasis, and tumour regulation . IL‐17‐producing γδ T cells, which belong primarily to the Vγ4 + subset, have a protective function against infection but lead to a deterioration of arthritis and promote breast cancer metastasis . IFN‐γ producing Vγ1 + γδ T cells are responsible for controlling various infections .…”

Monocyte-mediated defense against bacteria, fungi, and parasites

“…In the absence of TNF signaling, Ly6C lo macrophages accumulate within infected LNs and display a defect in killing parasites [145]. During visceral leishmanaisis, IL-17A production by γδ T cells suppresses Ly6C hi monocyte-dependent parasite killing in the liver [146]. In humans, both reactive oxygen and nitrogen species contribute to monocyte-dependent killing of Leishmania braziliensis [147].…”

A sinalização via NOD2-RIP2 modula a imunidade adaptativa contra <i>Leishmania infantum</i>

“…Our data show that Rorc is negatively modulated by L. infantum infection, indicating that the IL-17A detected after infection could be produced through a RORγt independent pathway as well. L. donovani infection, however, has γδ T cells as the major IL-17A source [34,35], which was not relevant for L. infantum.…”

“…The effective immunity to VL is characterized by the development of a robust parasite-specific Th1/IFN-γ response [2,3] in detriment of IL-10-producers patterns [4,5]. The role of IL-17A-producing cells, however, is controversial, but, at long term, it seems to play a protective role against VL through triggering the synthesis of leishmanicidal molecule by infected macrophages promoting parasite clearance [6][7][8]. The mechanism that coordinates the balance between Th1 and Th17 differentiation during VL is still a lack of understanding.…”