Microbial Infection-Induced Expansion of Effector T Cells Overcomes the Suppressive Effects of Regulatory T Cells via an IL-2 Deprivation Mechanism

Abstract

Regulatory Foxp3+ T cells are a critical cell population that suppresses T cell activation in response to microbial and viral pathogens. We identify a cell-intrinsic mechanism by which effector CD4+ T cells overcome the suppressive effects of Treg cells in the context of three distinct infections, Toxoplasma gondii, Listeria monocytogenes, and vaccinia virus. The acute responses to the parasitic, bacterial, and viral pathogens resulted in a transient reduction in frequency and absolute number of Treg cells. The infection-induced partial loss of Treg cells was essential for the initiation of potent Th1 responses and for host protection against the pathogens. The observed disappearance of Treg cells was a result of insufficiency in IL-2 caused by the expansion of pathogen-specific CD4+ T cells with a limited capacity of IL-2 production. Exogenous IL-2 treatment during the parasitic, bacterial, and viral infections completely prevented the loss of Treg cells, but restoration of Treg cells resulted in a greatly enhanced susceptibility to the pathogens. These results demonstrate that the transient reduction in Treg cells induced by pathogens via IL-2 deprivation is essential for optimal T cell responses and for host resistance to microbial and viral pathogens.

Vaccine-induced myeloid cell population dampens protective immunity to SIV

“…To explore the possible mechanisms by which the adjuvant-only group manifested better protection than did the vaccinated groups, we hypothesized that immune regulators such as Tregs and MDSCs are involved. Downregulation of negative regulators such as Tregs during acute infection has been shown to be essential for optimal T cell responses and host resistance to pathogens such as Toxoplasma gondii, Listeria monocytogenes, and vaccinia virus, and restoration of Tregs led to enhanced susceptibility to these pathogens (44). In this study, however, we found positive associations of set-point VLs only with MDSCs, but not with Tregs.…”

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

“…However, our data indicate that in Prf1 2/2 mice the level of CD8 1 T-cell immune activation crosses a critical threshold, at which point the CD8 1 T cells become capable of diverting the normally antiinflammatory IL-2 feedback loop into a proinflammatory circuit, driving the precipitous decrease in Treg cell numbers and feed-forward inflammation. Several synergistic events appear to participate in this process, with IL-2 production by CD4 1 T cells being suppressed 28 (an effect that might be mediated directly by IFN-g 29 ) and release of sCD25 by CD8 1 T cells and reversal of the CD25 expression hierarchy allowing preferential consumption of IL-2 by CD8 1 T cells at the expense of Treg cells. Critically, this inverted hierarchy meant that IL-2 supplementation, which is normally protective in patients with Treg cell deficiencies, drove excessive CD8 1 T-cell activation and led to the premature death of Prf1 2/2 mice.…”

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

“…IL-2/anti-IL-2 complexes were prepared as described in the literature (14,20) with minor modifications. Recombinant IL-2 and anti-IL-2 monoclonal antibody (MAb; clone JES6-1A12) were obtained from eBioscience.…”

“…They constitutively express the interleukin-2 (IL-2) receptor alpha chain (IL2R␣), a surface receptor also known as CD25, and the intracellular fork head box-p3 transcription factor (Foxp-3) marker (16). The role of Tregs after infection with type II strains has been fully described (14,(17)(18)(19)(20)(21), and Tregs have been clearly implicated in the mortality of C57BL/6 mice after oral infection in the lethal ileitis model (14). The collapse of Tregs is correlated with pathogenicity and occurs only under highly pathogenic conditions since oral infection of BALB/c mice with a type II strain did not induce a reduction in the levels of Tregs (14).…”