iiinova — where your digital self keeps evolving

Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

🛤️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! 🎉

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

👶⚖️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

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

🗣️ 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.

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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!📉

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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!!!

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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.

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

📑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?

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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!! 👶🔥

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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!

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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.

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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.

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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.🚼 🤔🤔

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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?

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 29/08/2025

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

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Reposted by Miguel Marín-Rodero, MD

Seth Thomas Scanlon @immunoeditor.bsky.social · 20/03/2025

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

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Reposted by Miguel Marín-Rodero, MD

Open Box Science @openboxscience.bsky.social · 19/03/2025

@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...

youtube.com

[Miguel Marin] The meninges host a distinct compartment of regulatory T cells that preserves brain

YouTube video by Open Box Science

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Reposted by Miguel Marín-Rodero, MD

Open Box Science @openboxscience.bsky.social · 03/03/2025

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...

hms.harvard.edu

Regulatory T Cells Found To Safeguard Brain Health, Memory Formation

Research identifies guardian cells dwelling in the protective layers of the brain

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Reposted by Miguel Marín-Rodero, MD

Open Box Science @openboxscience.bsky.social · 24/02/2025

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

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Reposted by Miguel Marín-Rodero, MD

Immunology Podcast @immunologypodcast.com · 19/02/2025

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

bit.ly

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.

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Reposted by Miguel Marín-Rodero, MD

Silvia Galvan Pena @galvanpenas.bsky.social · 29/01/2025

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!

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

12/ Last but not least, a special shoutout to my mentor, Diane Mathis, for trusting me, encouraging me to explore my ideas, and paving the way for this exciting new avenue at the CBBDM lab. 🙌

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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!

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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!

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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)!

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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🤔

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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!

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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! 🎨

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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.🤝

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

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.📷⚡

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Miguel Marín-Rodero, MD @mmr2.bsky.social · 28/01/2025

1/ New in #ScienceImmunologyResearch! We explored how the brain maintains equilibrium with the immune system. Our focus? The key player in immune tolerance and tissue function regulation: regulatory T cells (Tregs). Let’s dive in! www.science.org/doi/10.1126/... @immunoeditor.bsky.social

science.org

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.

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Reposted by Miguel Marín-Rodero, MD

Waggoner Lab @labwaggoner.bsky.social · 28/01/2025

Meningeal regulatory T cells restrain local interferon-γ–producing lymphocytes, thereby safeguarding parenchymal brain homeostasis @sciimmunology.bsky.social @mmr2.bsky.social www.science.org/doi/10.1126/...

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