T cell Suppression In Vitro During Toxoplasma gondii Infection is the Result of IL‐2 Competition Between Tregs and T cells Leading to Death of Proliferating T cells

Abstract

A reduced proliferation to T cell mitogens is observed in vitro in murine cells isolated during the acute phase of Toxoplasma gondii infection. Foxp3 + regulatory T cells (Tregs) mediate this suppression, which is interleukin (IL)-2 dependent. In this work, we analysed the mechanism of this Treg-mediated suppression. We found that removal of antigen-presenting cells (APC) from spleen cells from infected mice did not modify suppression but further elimination of Tregs led to a restored proliferation, demonstrating that Tregs mediate suppression in the absence of APC. Production of IL-2 by T cells from infected animals was abolished but partially restored when Tregs were removed. However, IL-2 levels and T cell proliferation were restored when Tregs and T cells were separated by transwells, indicating that Tregs require close proximity with T cells to induce suppression. Tregs from infected mice were able to reduce proliferation of CTLL-2 cells in the classical IL-2 bioassay, strongly suggesting that Tregs compete with T cells for IL-2. We found that T cells from infected mice died after a few rounds of division in vitro, but addition of recombinant IL-2 or removal of Tregs abolished this effect. Our results showed that suppression of T cell proliferation during acute Toxoplasma gondii infection is the result of death of proliferating T cells by Treg-mediated IL-2 competition. Thus, immunosuppression is due to death of proliferating T cells as a consequence of low IL-2 availability.

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

“…It was also demonstrated that TReg expansion with JES6-1A12-containing IL2C can overcome the competition for bioavailable IL-2 by regulatory and effector T cells, leading to reduced immunopathology and morbidity during acute Type II T. gondii ME49 infection [40]. These studies are in line with other reports showing a collapse of TReg cells during acute T. gondii infection due to IL-2 starvation and an overall protective role of TRegs in acute T. gondiimediated immunopathogenesis [75][76][77][78]. In contrast to JES6-1A12-containing IL2C, S4B6containing IL2C has been shown to boost NK cell and memory CD8 + T cell numbers in mice and to enhance their cytolytic capacity against viral infections, malaria [79] and cancer cells [71,[80][81][82].…”

A long-lasting protective immunity against chronic toxoplasmosis in mice induced by recombinant rhoptry proteins encapsulated in poly (lactide-co-glycolide) microparticles

“…CTL response driven by IFN-γ could induce cell apoptosis of the infected cell and then clear the intracellular protozoan (Suzuki et al 1988;Niedelman et al 2013). IL-2 is necessary for the growth, proliferation, and differentiation of T cells and is involved in preventing parasitic invasion combined with IFN-γ ( Matowicka-Karna et al 2009;Salinas et al 2014). The increasing levels of IFN-γ and IL-2 in mice immunized with protein vaccines observed in the present study indicated an efficient protection against chronic toxoplasmosis induced by rhoptry proteins.…”

Role of CD4+Foxp3+Regulatory T Cells in Protection Induced by a Live Attenuated, Replicating Type I Vaccine Strain of Toxoplasma gondii

“…A reduced number of Tregs during the acute phase of T. gondii infection is a consequence of a reduced IL-2 availability (14,19). IL-2 is also involved in the transient immunosuppression observed during acute toxoplasmosis (24,25).…”

“…Moreover, the main sources of IL-10 in both groups were the CD4 Ϫ cells, since the percentages of CD4 ϩ cells among IL-10-producing cells in two different experiments were 28% and 30% for the RH and the Mic1.3KO groups, respectively. IL-2 is a cytokine that is essential for Treg development and survival (23) and is also involved in the immunosuppression induced during the acute phase of toxoplasmosis (24,25). IL-2 levels were quantified in spleen culture supernatants after activation with anti-CD3 (data not shown).…”