And more importantly…🗣️ VAT ST2+ Tregs could restore insulin sensitivity!
In our preadolescent diet-switch model, mice with partial Treg recovery (LHL) showed total normalization of their insulin tolerance ,despite prior HFD exposure!📉

We modeled adolescent obesity starting in the perinatal window 👶🍔 and asked: can VAT Tregs bounce back or resist HFD if LFD is introduced in time?
🥁 Yes! ST2⁺ VAT Tregs partially rebounded, showing lingering capacity to resist HFD, expand, and control VAT inflammation!!!

In LHL, even without falling back—despite weight loss, normal glucose, and improved GTT, mice lacking VAT Tregs stayed insulin resistant 🤯 → a lasting immunometabolic “scar” from perinatal Treg loss.

We wanted to test this in a real-life setting: diet cycling (start a diet, then fall back).
We used HFD to deplete VAT Tregs, then cycled mice through 12 wks of LFD/HFD (LLL, LHH, LLH, LHL) ➡️ mimicking human diet patterns.
🔥Any HFD exposure caused dramatic VAT Treg (ST2+) loss

But when we depleted Tregs in the perinatal period… NOTHING CHANGED🫨
Perinatal Tregs refilled tissue niches in ways adult-derived Tregs couldn't
This showed tissue-specific reliance on neonatal vs. adult Tregs ⏩ with VAT the most dependent.
Let’s dig in!! 👶🔥

8 weeks after punctual Treg depletion, 3 patterns emerged:
🚫 No recovery → VAT & ear skin (no ST2+ Tregs)
📈 Overshoot → meninges & lung
➖ Stable → liver, kidney, others

⚕️Clinical settings:Total body irradiation☢️+ bone marrow transplant showed strikingly similar dynamics!

Results:
1️⃣ Perinatal Tregs seeded all tissues—but not equally! They were enriched in visceral adipose tissue (VAT) and meninges, and they preferentially expressed ST2 in every tissue.
2️⃣ Progenitors showed bias: perinatal P1 favored VAT & meninges, while P2 spread more evenly.

We turned to the thymus, where Tregs are generated. Two progenitors:
• Foxp3⁻CD25⁺ (P1)
• Foxp3⁺CD25⁻ (P2)
P1 was enriched perinatally...👀
Could this explain adult vs perinatal Tregs?
❌Unlikely, their transcriptomes (identity) stayed stable over time. So what else can be?

11/ Finally, a huge thank you to the @Scimmunology editors for their constructive feedback, our amazing collaborators, and the incredible CBDM team and friends for their support, coffee chats, and endless motivation! ☕✨
cbdm.hms.harvard.edu

#Neuroimmunology

10/ How do Tregs regulate T cell activation and IFNγ in the meninges? 🧠 They control free IL-2 via the high-affinity IL-2 receptor, CD25. Blocking IL-2 (Treg depletion) and adding excess IL-2 (bypassing Tregs) helped us to unravel this fine-tuning mechanism!

9/ Hippocampal RGL cells died, causing short-term memory impairment for up to 8 weeks! 💀But the V-SVZ stem cells were unaffected & no T cell infiltration. Blocking IFNγ in the meninges rescued RGL cell death—restoring it to Treg-present levels, despite T cell infiltration!

8/ Treg removal from meninges in the hippocampus reduced neurogenesis pathways and activated glia (microglia, astrocytes, OPCs)—without BBB leakage! 🗣️ T cells entered via the velum interpositum, persisting even with S1PR1 blockade (FTY720)!

7/ Why intriguing? The hippocampus is critical for functions like learning and memory and is one of only two regions in the adult brain with active neurogenesisis (via radial glia-like cells). Diseases like Alzheimer’s disrupt this region, leading to memory loss and dementia🤔

6/ But what about the brain?We observed sharp immune cell infiltration—mainly T cells and NK cells—along with increased IFNγ sensing and changes in neuronal activation. Surprisingly, most of these changes were concentrated in the hippocampus!

5/ But do they matter? To find out, we used short-term Treg depletion (Foxp3-DTR) and intracisterna magna anti-CD25 injections. The outcome? T cells cells expanded, IFNγ surged (mainly from T and NK cells), and meningeal IgD+ B cells dropped🔥
Image

4/ scRNAseq & flow cytometry showed that meningeal Tregs consist of 3 populations:
1️⃣ Quiescent
2️⃣ Tfr Tregs (controlling B cell responses)
3️⃣ Th1-like Tregs (the largest group), specialized in managing type 1 immune responses, like IFNγ—the main "flavor" of the meninges! 🎨

3/ The meninges—the largest brain border region—host a newly identified, unique tissue Treg population. These Tregs cluster around the sinuses and are located near MHCII+ cells, primarily cDC2.🤝

2/ 🔬Tregs in the meninges are crucial immune regulators! They control IFNγ levels, block T cell infiltration into the hippocampus, and protect RGL cells from death—preventing persistent short-term memory impairment.📷⚡