Eosinophils, but Not Type 2 Innate Lymphoid Cells, Are the Predominant Source of Interleukin 4 during the Innate Phase of Leishmania major Infection

Abstract

Interleukin (IL)-4 plays a central role in the initiation of a type 2 T helper cell (Th2) response, which leads to non-healing and progressive infections with the protozoan parasite Leishmania (L.) major. Here, we tested the hypothesis that type 2 innate lymphoid cells (ILC2), which promote the development of Th2 cells, form an important source of IL-4 early after intradermal or subcutaneous L. major infection. Lineage-marker negative CD90.2+CD127+PD1− ILC2 were readily detectable in the ear or foot skin, but hardly in the draining lymph nodes of both naïve and L. major-infected self-healing C57BL/6 and non-healing BALB/c mice and made up approximately 20% to 30% of all CD45+SiglecF− cells. Dermal ILC2 of C57BL/6 mice expressed the inducible T cell-costimulator (ICOS, CD278), whereas BALB/C ILC2 were positive for the stem cell antigen (Sca)-1. Within the first 5 days of infection, the absolute numbers of ILC2 did not significantly change in the dermis, which is in line with the unaltered expression of cytokines activating (IL-18, IL-25, IL-33, TSLP) or inhibiting ILC2 (IL-27, IFN-γ). At day 5 to 6 post infection, we observed an upregulation of IL-4, but not of IL-5, IL-10 or IL-13 mRNA. Using IL-4-reporter (4get) mice, we found that the production of IL-4 by C57BL/6 or BALB/c mice was largely restricted to CD45+SiglecF+ cells of high granularity, i.e., eosinophils. From these data, we conclude that eosinophils, but not ILC2, are a major innate source of IL-4 at the skin site of L. major infection.

Chemokine receptors on human regulatory T cells during cutaneous leishmaniasis

“…4 Upon infection, innate immune cells such as neutrophils monocytes and NK cells are activated in an attempt to control infection and instruct an adaptive response. 6,7 IFNγ derived from NKs, cytotoxic CD8 T cells and CD4 Th1 cells is fundamental to activate a respiratory program with nitric oxide (NO) species in infected macrophages. 8,9 In this inflammatory context, regulatory T cells (Tregs) are necessary to regulate the immune response by diverse mechanisms.…”

“…Host's intrinsic immunological factors are key to determine the clinical presentation of the disease 4 . Upon infection, innate immune cells such as neutrophils monocytes and NK cells are activated in an attempt to control infection and instruct an adaptive response 6,7 . IFNγ derived from NKs, cytotoxic CD8 T cells and CD4 Th1 cells is fundamental to activate a respiratory program with nitric oxide (NO) species in infected macrophages 8,9 .…”

“…6 cells per tube) were suspended in PBS with 0.5% of BSA (termed PBS-W) and labelled with anti-CD4 PECy7 conjugated (Clone RPTA-4, mice IgG1κ), CD25 APC conjugated (Clone M-A251, mice IgG1κ), CCR-4 APC conjugated (Clone 205,410, mice IgG2β), CCR-5 APC conjugated (Clone 3A9, rat IgG2aκ), and CCR7 APC conjugated (Clone 3D12, mice IgG2a) surface antibodies by 30 min at RT. Multiple tubes were prepared due to the limited configuration of the flow cytometer.…”

Dermis resident macrophages orchestrate localized ILC2-eosinophil circuitries to maintain their M2-like properties and promote non-healing cutaneous leishmaniasis

“…In the current studies, targeting IL-5 + ILC2s for deletion in the R5 : ROSA26iDTR or R5 : Gata f/f mice led to the reduced number of eosinophils, with downstream effects on the number of dermal TRMs due to the loss of a critical source of IL-4 required for their maintenance. A recent report confirmed eosinophils as the main intra-lesional source of IL-4 in L. major infected, C57BL/6 mice 39 . Evidence that IL-4/13 from eosinophils contributed to the upregulation of Tslp expression in dermal TRMs was provided by the scRNA-seq comparisons of relative Tslp expression within the dermal TRM cluster from infected, wild type and eoCre : IL4/13 f/f mice.…”

Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization

“…Despite the ILC2 predominance, in mouse skin lesions caused by L. major infection, it has been shown that eosinophils, rather than ILC2 cells, were the main source of IL-4 during the early stages of the disease [69]. IL-4 is a crucial factor in the expansion and differentiation of Th2 cells, which are critical for inducing alternative macrophage polarization.…”