Abstract
Foxp3+ regulatory T (Treg) cells are broadly divided into naive-like and activated Treg cells, however recent studies suggest further Treg cell heterogeneity. Treg cells contribute to impaired T cell responses in chronic infections, but the role of specific Treg cell subpopulations in viral infections is not well defined. Here, we report that activated Treg cells are separated into two transcriptionally distinct subpopulations characterized by low or high expression of the transcriptional regulator Id3. Id3lo Treg cells are a highly suppressive Treg cell subpopulation, expressing elevated levels of immunomodulatory molecules and are capable of broadly targeting T cell responses. Viral infection and interleukin-2 promote the differentiation of Id3hi into Id3lo Treg cells and during chronic infection Id3lo Treg cells are the predominant Treg cell population. Thus, our report provides a framework, in which different activated Treg cell subpopulations specifically affect immune responses, possibly contributing to T cell dysfunction in chronic infections.
Highlights
CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining immune homeostasis and self-tolerance due to their ability to suppress T cell responses
Gene set enrichment analysis (GSEA) of the transcriptional profiles of Id3lo and Id3hi Treg cells with the Treg cell transcriptional signature [30] showed no differences in the expression of Treg cell signature genes (Figure 1d), confirming that both subpopulations belong to the Treg cell lineage
We identified a highly suppressive Treg cell subpopulation characterized by low expression of the transcriptional regulator Id3, which (1) defined a subpopulation of activated CD44hi Treg cells, (2) had a transcriptional profile of late-stage differentiated effector Treg cells, (3) expressed high levels of inhibitory surface receptors and immunosuppressive cytokines and (4) was superior in suppressing proliferation and differentiation of T cells compared to CD44hiId3hi Treg cells
Summary
CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining immune homeostasis and self-tolerance due to their ability to suppress T cell responses. Mice and humans lacking Treg cells suffer from autoimmune and inflammatory disorders [1, 2]. Besides their well-established role in suppressing autoreactive T cells, Treg cells fulfill diverse roles promoting or preventing effective immune responses upon infection [3]. Treg cell abundance is tightly balanced for optimal pathogen-specific responses [3]. Treg cell numbers are transiently decreased in many acute infections to allow an optimal immune response and increased Treg cell numbers or activity can impair effector T cell responses resulting in pathogen persistence. The appropriate magnitude and quality of the Treg cell response can be beneficial for the host by allowing the localization of effector immune www.impactjournals.com/oncotarget cells into lymph nodes and infected tissues [8] and by supporting memory T cell formation [9,10,11]
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