Thank you!:)

@pnas.org

🛤️This journey took me from central tolerance in the thymus to exploring tissue immunology & immunometabolism
🙌Huge thanks to Tesh for making this shared project stimulating, fun & engaging throughout— & to the CBDM crew + my PI Diane for their trust & support! 🎉

👶⚖️Big picture: the perinatal period is key for building tissue Treg networks across the body. Some tissues—like fat —depend on them most to stay healthy. This highlights how the earliest stages of life shape long-term health, and how early disruptions can leave lasting scars

🗣️ Our findings show that perinatally generated eVAT Tregs control insulin sensitivity, while glucose tolerance tracks more with body weight
♟️⚡️ These Tregs prevent lasting metabolic dysfunction—making their preservation key to effective obesity prevention.

The pediatric obesity crisis raises early risk for diabetes, MASH, heart disease, and mental health issues.
In response,the American Academy of Pediatrics
now recommends shifting from “watchful waiting” to early, intensive interventions to prevent long-term harm- but how they work remains unclear

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

📑VAT Tregs maintain homeostasis—controlling inflammation, insulin sensitivity & adipocyte maturation
🍔 HFD flips the switch: ~12 wks in, obesity drives VAT Treg loss → inflammation + insulin resistance 🔥
🤔But are perinatal Tregs the key players—or can any Tregs do the job?

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!

Perinatal Tregs👶 are uniquely generated in the first 3 wks of life—they are the first to arrive to tissues!!! 👉 Are they forming IRREPLACEABLE interactions within those niches that adult waves cannot?🫂
To test this, we depleted tissue Tregs in both adult and perinatal mice.

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.

What about where they go? 🗺️ We used two approaches:
1️⃣ Treg lineage tracing (🟢➡️🟡) in the first week of life, then checked at 15 wks.
2️⃣ Intrathymic injection of day-5 congenitally-labeled Treg progenitors into day-5 hosts.🚼
🤔🤔

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?

Our lab’s earlier work (Yang et al., 2015) found two waves of Tregs:
• Perinatal (first 3 weeks)
• Adult-derived
They’re not interchangeable—perinatal Tregs rescued autoimmunity, adult Tregs could not!
❓But what makes them so especial