Pathologic Th1–Treg Cells Exacerbate Acute Lung Injury and Lethality in Sepsis

TL;DR

A specific type of immune cell worsens lung damage and death in sepsis, and targeting these cells could help treat the condition.

Contribution

Identifies Th1-Treg cells as pathogenic in sepsis and reveals their induction via the eCIRP–TLR4–STAT1/5 axis.

Findings

Th1-Treg cells accumulate in the lungs of septic mice and exacerbate acute lung injury.

eCIRP induces Th1-Treg cells through TLR4 and STAT1/STAT5 signaling.

Adoptive transfer of Th1-Treg cells increases mortality in septic mice.

Abstract

What are the main findings?
eCIRP induces Th1-Treg cells via the TLR4-STAT1/STAT5 signaling axis in sepsis.Th1-Treg cells aggravate acute lung injury and mortality in sepsis.

eCIRP induces Th1-Treg cells via the TLR4-STAT1/STAT5 signaling axis in sepsis.

Th1-Treg cells aggravate acute lung injury and mortality in sepsis.

What are the implications of the main findings?
The findings provide novel mechanistic insight into sepsis by defining the pathogenic role of an underappreciated T cell subset.Targeting pathogenic Th1-Treg cells potentially alleviates sepsis-induced acute lung injury.

The findings provide novel mechanistic insight into sepsis by defining the pathogenic role of an underappreciated T cell subset.

Targeting pathogenic Th1-Treg cells potentially alleviates sepsis-induced acute lung injury.

Sepsis is characterized by dysregulated immune responses induced by damage-associated molecular patterns, such as extracellular cold-inducible RNA-binding protein (eCIRP), that frequently lead to acute lung injury (ALI) and high mortality. Recently, a subset of CD4+ T cells possessing both T helper 1 (Th1) and regulatory T cell (Treg) phenotypes, termed Th1-Treg cells, has been identified; however, their function in sepsis remains unknown. In this study, we investigated the dynamics, induction mechanisms, and functional roles of Th1-Treg cells in the development of sepsis-induced ALI. Polymicrobial sepsis was induced in mice using cecal ligation and puncture. In vivo, Th1-Treg cell accumulation in the lungs was analyzed in WT and CIRP−/− mice following sepsis. In vitro, isolated CD4+ T cells from WT and TLR4−/− mice were treated with eCIRP to evaluate Th1-Treg cell differentiation and downstream signaling pathways. STAT1 and STAT5 activation were evaluated, and pharmacological inhibitors were used to assess their involvement. Adoptive transfer of Th1-Treg cells was conducted to determine their functional impact on ALI and mortality in septic mice. We observed a significant accumulation of Th1-Treg cells in the lungs of WT septic mice compared to sham mice. eCIRP drove the induction of Th1-Treg cells in vitro, and CIRP−/− mice exhibited decreased Th1-Treg cell accumulation in the lungs compared to WT mice after sepsis. In parallel to Th1-Treg cell induction, eCIRP activated signal transducer and activator of transcription, STAT1 and STAT5. Both the induction of Th1-Treg cells and the activation of STAT1/5 proteins were significantly attenuated in TLR4−/− mice. Furthermore, pharmacological inhibition of STAT1/5 signaling significantly reduced eCIRP-induced Th1-Treg cell differentiation. Intriguingly, adoptive transfer of Th1-Treg cells significantly exacerbated ALI, resulting in increased mortality in sepsis. Our findings indicate Th1-Treg cells induced by the eCIRP–TLR4–STAT1/5 axis aggravate ALI, worsening mortality in sepsis. Targeting these pathogenic cells potentially alleviates sepsis-induced ALI.

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