Abstract
While it is now acknowledged that CD4+ T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by Trypanosoma cruzi was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental T. cruzi infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during T. cruzi infection, we transferred in vitro differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8+ T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of T. cruzi infection enables the emergence of protective anti-parasite CD8+ T cell immunity and critically influences host resistance.
Highlights
Regulatory T (Treg) cells, defined by the expression of the lineage transcription factor forkhead box P3 (Foxp3), are able to suppress most immune cells [1] and their suppressive function is crucial for immune homeostasis and prevention of autoimmunity [2]
We studied in detail the kinetics of Treg cell responses using Foxp3-EGFP reporter mice and demonstrated that frequency of Treg cells is reduced along T. cruzi infection in most peripheral organs including spleen, liver and inguinal lymph nodes
Not surprising considering the current views on peripheral Treg (pTreg) cell induction [71], we demonstrated that the inflammatory environment triggered by T. cruzi limits the peripheral induction of Treg cells
Summary
Regulatory T (Treg) cells, defined by the expression of the lineage transcription factor forkhead box P3 (Foxp3), are able to suppress most immune cells [1] and their suppressive function is crucial for immune homeostasis and prevention of autoimmunity [2]. The role of this cell subset appears to be different between acute and chronic infections and even to change during the same infection with the transition from acute to chronic stages In this way, Treg cells have been shown to coordinate early protective immunity to mucosal Herpes Simplex Virus [7, 8] and pulmonary Respiratory Syncytial Virus [9, 10], and to sustain memory CD8+ T cell immunity to West Nile virus [11]. During leishmaniasis [17] and malaria [18], Treg cells have been shown to limit the magnitude of effector responses, resulting in failure to adequately control infection [19,20,21] These cells favor host resistance during infections with S. mansoni and T. gondii by restraining collateral tissue damage caused by vigorous anti-parasite immune responses [22,23,24]. The impact of Treg cells in the outcome of an infection is expected to be different depending on the pathogen, timing and affected tissues, while their manipulation may open up new avenues for therapeutic strategies
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