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

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.