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Seeding of visceral adipose tissue with perinatally generated regulatory T cells shapes the metabolic tenor in mice | PNAS www.pnas.org/doi/10.1073/...

@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

New in
@PNASNews
!🗞️🆕Perinatally generated regulatory T cells (Tregs) seed visceral adipose tissue and set the metabolic tenor in mice. Early-life Treg layers persist and shape insulin sensitivity later in life! #Perinatal #Tregs #Metabolism #Obesity #Diet

Check out this just-released Gustavo Gastão Davanzo & @jonykipnis.bsky.social News & Views piece in Nature Immunology covering recent research by @mmr2.bsky.social, Diane Mathis, & colleagues in Science Immunology!

Marin-Rodero et al. Sci Immunol 2025
science.org/doi/10.1126/sciimmunol.adu2910

The brain’s regulators Nature Immunology - Once seen as a passive barrier, the dura mater is now recognized as an active immune site. A study now suggests that regulatory T cells within the dura mater modulate immune...

Our News&Views on the recent exciting paper from Diane Mathis & Christophe Benoist Lab || rdcu.be/eebrL

[Miguel Marin] The meninges host a distinct compartment of regulatory T cells that preserves brain YouTube video by Open Box Science

@mmr2.bsky.social talk is now on YouTube!
"The meninges host a distinct compartment of regulatory T cells that preserves brain homeostasis "
CBDM lab @HarvardMed
www.youtube.com/watch?v=eZTP...

Regulatory T Cells Found To Safeguard Brain Health, Memory Formation Research identifies guardian cells dwelling in the protective layers of the brain

An exciting talk is waiting for you next Thursday 12pm EST. 🎙️ Speaker @mmr2.bsky.social
will be taking about new roles of Treg in health and disease from the Diane Mathis & Christophe Benoist Lab
@HarvardMed Registration👇 us02web.zoom.us/j/889479660. hms.harvard.edu/news/regulat...

OBS #Immunology Seminar
📆 Thu, 03/06, 12pm ET/6 pm CET
"The meninges host a distinct compartment of regulatory T cells that preserves brain homeostasis "
🎙️ Speaker: @mmr2.bsky.social Harvard Medical School

📣 Moderator: @eugecc.bsky.social - UNAM
Registration👇
buff.ly/43cGl7q

The meninges host a distinct compartment of regulatory T cells that preserves brain homeostasis Meningeal regulatory T cells restrain local interferon-γ–producing lymphocytes, thereby safeguarding parenchymal brain homeostasis.

Our latest episodes features a discussion on #Tregs in the #meninges! 💀

Read the paper from Dr. Miguel Marín-Rodero (@mmr2.bsky.social) and a team in Dr. Diane Mathis' lab: bit.ly/3CMAWJp

Stream the episode: bit.ly/4jUqeB4

Thank yo so much!🙏🏽

Thanks!!❤️❤️

The Galvan-Pena lab is hiring a postdoc! If you know of any PhD students who will graduate soon or have recently graduated, and are interested in gut immunology and systemic effects of the microbiome - please send them my way!

Thank you!🙏🏽