Neonatal liver niches program T cell tolerance

2026 · doi:10.64898/2026.01.13.698576
preprint OA: closed
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⚙ AI-generated deep summary by claude@2026-07, 2026-07-03 · read from full text ⓘ

The paper studies how the immune system establishes tolerance after birth, focusing on the neonatal liver in postnatal week 1–2. Using mechanistic experiments, the authors find that the neonatal liver undergoes a microbiota-independent expansion of regulatory T cells (Tregs) alongside a distinct, microbiota-tuned wave of activated conventional CD4+ T cells, and that this Treg expansion depends on MHCII-mediated antigen presentation by CCR7+ cDC1 dendritic cells forming tolerogenic DC:T cell clusters. They further report that PD-L1 checkpoints selectively increase Tregs without unleashing conventional T cells, and that the transient neonatal program both predisposes hepatotropic viral infections to chronic disease and protects the adult liver from steatotic disease, with the key caveat being that these effects are timing-dependent to the neonatal window. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

After birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we characterize the neonatal liver as a central hub in this process: In postnatal week 1–2, the liver hosts a developmentally encoded, microbiota-independent expansion of regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4⁺ T cells (Tconvs). Mechanistically, the Treg expansion is governed by MHCII-mediated antigen presentation by CCR7+ cDC1s, which establish tolerogenic DC:T cell clusters in the liver parenchyma, allowing for local expansion and control via PD-L1 checkpoints that selectively increase Tregs without unleashing Tconvs. Importantly, this transient, neonatal program predisposes hepatotropic viral infections to progress toward chronic disease but also protects the adult liver from steatotic disease. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions.
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Abstract After birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we characterize the neonatal liver as a central hub in this process: In postnatal week 1–2, the liver hosts a developmentally encoded, microbiota-independent expansion of regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4⁺ T cells (Tconvs). Mechanistically, the Treg expansion is governed by MHCII-mediated antigen presentation by CCR7+ cDC1s, which establish tolerogenic DC:T cell clusters in the liver parenchyma, allowing for local expansion and control via PD-L1 checkpoints that selectively increase Tregs without unleashing Tconvs. Importantly, this transient, neonatal program predisposes hepatotropic viral infections to progress toward chronic disease but also protects the adult liver from steatotic disease. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions. Competing Interest Statement The authors have declared no competing interest.

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