The p110δ Isoform of Phosphatidylinositol 3-Kinase Controls Susceptibility to Leishmania major by Regulating Expansion and Tissue Homing of Regulatory T Cells

Abstract

Resistance to Leishmania major and most intracellular pathogens is usually associated with a strong T cell-mediated immunity, particularly a CD4(+) Th1 response. Mice with an inactivating knock-in mutation in the p110delta isoform of PI3K (referred to as p110delta(D910A)) show severely impaired T cell responses. Because a strong T cell response is thought to mediate resistance to intracellular pathogens, we examined the outcome of L. major infection in p110delta(D910A) mice. Paradoxically, p110delta(D910A) mice on "resistant" and "susceptible" genetic backgrounds showed more robust resistance manifested as significantly reduced lesion size and accelerated parasite clearance. This enhanced resistance was associated with dramatically diminished immune responses, including impaired cell proliferation and effector cytokine (IFN-gamma and TNF) production. Interestingly, the ability of macrophages and dendritic cells from p110delta(D910A) mice to produce NO and destroy Leishmania parasites was similar to those of wild-type mice. We show that the enhanced resistance of p110delta(D910A) mice was due to impaired expansion and effector functions of regulatory T cells (Tregs). Adoptive transfer studies demonstrated that p110delta(D910A) mice lost their increased resistance when given enriched Tregs from wild-type mice. We suggest on the basis of these and further observations that the lack of this enzyme prominently affects Treg expansion and homing to infection sites, and that in the absence of Tregs, weak Th1 responses are capable of containing parasites and prevent pathology. We also suggest that temporary pharmacological inhibition of this enzyme may be a very effective form of treatment against cutaneous leishmaniasis.

Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis

“…A recent study by Liu et al (27) has found that PI3Kδ also controls susceptibility to CL caused by L. major by regulating the expansion and tissue homing of the Tregs that are involved in pathogenesis (27). In the present study, we found that although PI3Kγ blockade/deficiency significantly reduced recruitment of Tregs to the lesion, it had no effect on development, expansion, or IL-10 production from these cells.…”

“…In the present study, we found that although PI3Kγ blockade/deficiency significantly reduced recruitment of Tregs to the lesion, it had no effect on development, expansion, or IL-10 production from these cells. Interestingly, Liu et al (27) found that PI3Kδ was not involved in mediating uptake of parasites into host phagocytes. This is perhaps not surprising, because both PI3Kγ and PI3Kδ, which are primarily expressed in hematopoietic cells and endothelial cells, have been reported to have related yet nonredundant roles.…”

“…Recently, Liu et al (27) reported that PI3Kδ, a class IA PI3K that regulates actin polymerization together with PI3Kγ, controls susceptibility to L. major by regulating expansion and tissue homing of Tregs. We therefore examined the effect of PI3Kγ blockade on recruitment and IL-10 production by CD4 + FoxP3 + Tregs in L. mexicanainfected C57BL/6 FoxP3-EGFP knock-in mice (Fig.…”

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

“…L-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin (Invitrogen Life Technologies, Burlington, Ontario, Canada). For infection, mice were injected in the right hind footpad with 5 × 10 6 stationary phase promastigotes in 50 μL PBS as previously described [38]. Lesion sizes were monitored weekly by measuring footpad swellings with calipers.…”

“…Six to 8 weeks old homozygous PIP KO mice (backcrossed >9 generations into CD1 background) and WT CD1 mice were obtained from our in-house breeding colony managed by the Central Animal Care Services, University of Manitoba. All animal experiments were approved by the University of Manitoba stationary phase promastigotes in 50 μL PBS as previously described [38]. Lesion sizes were monitored weekly by measuring footpad swellings with calipers.…”