Abstract
CD4+ Foxp3+ regulatory T cells (Tregs) not only enforce peripheral tolerance and restrain self-reactive immune responses, but also maintain organismal homeostasis and safeguard the function of parenchymal tissues. A paradigmatic tissue–Treg population resides in the visceral adipose tissue (VAT) and regulates organismal metabolism by interacting with adipocytes and local immunocytes. Compared with their lymphoid-tissue counterparts, VAT–Tregs have a distinct T cell receptor (TCR) repertoire and transcriptional profile, allowing them to maintain and function in the unique tissue microenvironment. However, when, where, and how VAT–Tregs acquire their distinct features and what signals drive their phenotypic diversification have just started to be unraveled. Here we summarize the recent advances in our understanding on the mechanisms of VAT–Treg derivation and differentiation. We discuss the origin and life history of VAT–Tregs, review the identification and characterization of a VAT–Treg precursor population in the secondary lymphoid organs, and highlight a stepwise reprogramming model of VAT–Treg differentiation that involves multiple stages at distinct locations. Lastly, we discuss whether a similar process may also be involved in the differentiation of Tregs from other non-lymphoid tissues and the imperative questions that remain to be addressed.
Highlights
Foxp3+ regulatory T cells (Tregs) are a subset of CD4+ T cells that are crucial for maintaining immune tolerance [1]
A fundamental, but difficult to answer, set of questions about visceral adipose tissue (VAT)–Tregs and non-lymphoid tissues (NLTs) Tregs in general relates to their origin, derivation, and differentiation: Where do VAT–Tregs come from? How are they recruited to the adipose tissue and sustained therein? When, where and how do they take on their distinct phenotypes? Here we review recent progress on these important issues
Examining the precursor population by surrogate markers such as NFIL3 and KLRG1 in Ppargflox Foxp3-Cre mice that lack PPARg in Tregs will be informative to determine whether PPARg is just a marker for VAT–Treg precursors or required for the induction/maintenance of this population
Summary
Foxp3+ regulatory T cells (Tregs) are a subset of CD4+ T cells that are crucial for maintaining immune tolerance [1]. Treg population further revealed that they have partially acquired the VAT–Treg phenotype, upregulating gene signatures of Treg activation (e.g., Cd44, Klrg1, Prdm1, Batf), cytokine sensing (e.g., Il1rl1, Il9r), and migration to NLTs (e.g., Ccr2, Ccr3, Ccr8), while downregulating genes associated with lymphoid tissue trafficking (e.g., Ccr7, Sell) and resting state (e.g., Tcf7, Lef1).
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