IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells

Abstract

Parasitic helminths establish chronic infections in mammalian hosts. Helminth/Plasmodium co-infections occur frequently in endemic areas. However, it is unclear whether Plasmodium infections compromise anti-helminth immunity, contributing to the chronicity of infection. Immunity to Plasmodium or helminths requires divergent CD4+ T cell-driven responses, dominated by IFNγ or IL-4, respectively. Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines. Whether such plasticity occurs during co-infection is unclear. In this study, we observed reduced anti-helminth Th2 cell responses and compromised anti-helminth immunity during Heligmosomoides polygyrus and Plasmodium chabaudi co-infection. Using newly established triple cytokine reporter mice (Il4gfpIfngyfpIl17aFP635), we demonstrated that Il4gfp+ Th2 cells purified from in vitro cultures or isolated ex vivo from helminth-infected mice up-regulated IFNγ following adoptive transfer into Rag1–/– mice infected with P. chabaudi. Functionally, Th2 cells that up-regulated IFNγ were transcriptionally re-wired and protected recipient mice from high parasitemia. Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells. Finally, blockade of IL-12 and IFNγ during co-infection partially preserved anti-helminth Th2 responses. In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection. Consequently, co-infection with Plasmodium spp. may contribute to the chronicity of helminth infection by reducing anti-helminth Th2 cells and converting them into IFNγ-secreting cells.

Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity

“…Under these conditions, Th22 and Th17 cells maintained their respective expression patterns. To assess whether Th22 cells ever transition through a Th17 differentiation pathway, we employed a fate reporter mouse ( Il17a FP635 ; IL-17A tracer) 25, in which IL-17A expression results in the permanent expression of the red fluorescent protein FP635. As expected, Th17 cells co-expressed IL-17A protein and Il17a FP635 fate reporter, and a subset of cells under Th17 conditions expressed Il17a FP635 , but no longer expressed IL-17A (Fig.…”

Interferon Lambda: Modulating Immunity in Infectious Diseases

“…Several research groups confirm that IFN-λs influence the T-helper cell balance, which is shifted toward Th1 (70,71,(73)(74)(75)(76). The Th1/Th2 balance might be important for controlling specific infections such as helminths (6,77,78). In addition, the B-cell-driven humoral immune responses are also modulated by the presence of Th2 cytokines, e.g., during vaccination.…”

“…The role of IFN-λs in parasitic and fungal disease has not yet been explored. Although somewhat speculative, helminth infections in particular might be regulated by SNPs in the IFN-λ system, considering the profound evidence on the importance of Th1/ Th2 balance (6,77,78). Furthermore, for parasite infections of the liver such as Plasmodium spp.…”

Th1/Th2 cytokine expression in diabetic retinopathy

“…By secreting IL-4 and IL-10, Th2 cells can suppress immune damage caused by Th1 and stimulate B cell differentiation to plasma cells. The plasma cells can secrete antibody and generate memory B cells to enhance the humoral immune response (Coomes et al, 2015). In DR, increase in IL-2 and TNF-a expression and the decrease of IL-4 and IL-10 secretion, leading to Th1/Th2 imbalance and DR pathological progress.…”