PPARγ marks splenic precursors of multiple nonlymphoid-tissue Treg compartments

Abstract

Foxp3+CD4+ regulatory T cells (Tregs) regulate most types of immune response as well as several processes important for tissue homeostasis, for example, metabolism and repair. Dedicated Treg compartments—with distinct transcriptomes, T cell receptor repertoires, and growth/survival factor dependencies—have been identified in several nonlymphoid tissues. These Tregs are specifically adapted to function and operate in their home tissue—When, where, and how do they take on their specialized characteristics? We recently reported that a splenic Treg population expressing low levels of the transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) contains precursors of Tregs residing in visceral adipose tissue. This finding made sense given that PPARγ, the “master regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in visceral adipose tissue but not in lymphoid tissues. Here we use single-cell RNA sequencing, single-cell Tcra and Tcrb sequencing, and adoptive-transfer experiments to show that, unexpectedly, the splenic PPARγlo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple nonlymphoid tissues beyond visceral adipose tissue, such as skin and liver. The existence of a general pool of splenic precursors for nonlymphoid-tissue Tregs opens possibilities for regulating their emergence experimentally or therapeutically.

Tissue Tregs and Maintenance of Tissue Homeostasis

“…Similar to Foxp3, PPARγ is also required to drive the specific phenotype of VAT Tregs and their accumulation, the activation of TCRs is a necessary and sufficient condition to induce PPARγ expression ( Cipolletta et al, 2012 ; Li et al, 2018 ). Recent research shows that a PPARγ lo Treg population in the spleen contains precursors of VAT Tregs and produces not only VAT Tregs but also other tissue Tregs, such as liver and skin ( Li et al, 2021 ). The last feature of VAT Tregs is growth factor dependence, especially related to IL-33 and IL-33 receptor ST2 ( Han et al, 2015 ; Kolodin et al, 2015 ).…”

Toward a Paradigm to Distinguish Distinct Functions of FOXP3+ Regulatory T Cells

“…In fact, both GATA3 and PPAR-g are essential for proper Treg cell function in homeostatic conditions (5659). Whereas GATA3 is known to promote Foxp3 stability in inflammatory environments (58), PPAR-g is essential for proper homing of nonlymphoid tissue-localized Treg cells (56). These findings demonstrate that although these transcriptional pathways likely play a role in the stability and location of prorepair Treg cells, their expression is unlikely to define a unique tissue-protective or -reparative Treg cell subset.…”

Phenotypic and Functional Diversity in Regulatory T Cells

“…Evidence suggests that Tregs acquire tissue Treg programming in a gradual, stepwise process that begins in the spleen and lymph nodes and is dependent on BATF ( Hayatsu et al, 2017 ; Miragaia et al, 2019 ; Delacher et al, 2020 ). A Treg population found in the spleen that expresses low levels of the transcription factor, PPARγ, develops into tissue Tregs at multiple sites including skin, VAT, and liver demonstrating that tissue Treg precursors develop in the spleen prior to immigration to their respective tissues ( Li et al, 2021a ).…”

“…Transfer of PPARγlo Tregs led to more efficient seeding of the VAT compared to PPARγ- Tregs, despite being recovered at similar rates in the spleen, supporting the idea that PPARγlo Tregs are likely the progenitors for VAT Tregs ( Li et al, 2018 ). However, a more recent study found that PPARγlo Tregs are the progenitors for Tregs in several non-lymphoid tissues other than VAT, including the liver and skin ( Li et al, 2021a ). It is unclear if Tregs seeding all tissues go through this PPARγlo intermediate.…”

“…In addition to TCR signaling, several other factors are also important for VAT Treg cell differentiation. As discussed above, PPARγ is important for seeding the VAT by Tregs ( Cipolletta et al, 2012 ) but is not important for the development of splenic VAT Treg cell precursors, as defined by KLRG1 and the IL-33 receptor, ST2 ( Li et al, 2021a ). While PPARγ expression is expendable for upregulation of ST2 in secondary lymphoid organs, PPARγ deficient Treg in the VAT do not properly upregulate ST2 ( Kolodin et al, 2015 ).…”