Sepsis-Induced Immunosuppression Is Marked by an Expansion of a Highly Suppressive Repertoire of FOXP3+ T-Regulatory Cells Expressing TIGIT.

Abstract

Although the literature shows that an increase in both the number and suppressive function of CD4+forkhead box P3 (FOXP3)+ T-regulatory cells (Tregs) during sepsis contributes to an immunosuppressed state, little is known about the identity of these cells. Using the sepsis mouse model of cecal ligation and puncture (CLP), we analyzed the frequency and molecular signature of the T-cell immunoglobulin and ITIM domain (TIGIT)+ and TIGIT- Treg subsets, using flow cytometry and quantitative polymerase chain reaction. In addition, ST2-/- and signal transducer and activator of transcription 6 (STAT6)-/- mice were submitted to CLP or recombinant interleukin 33 (IL-33) treatment to investigate the mechanism whereby TIGIT+ Tregs differentiate during sepsis. Sepsis was marked by the sustained expansion of the highly suppressive TIGIT+ Treg subset, which expresses Helios, neuropilin 1, and high levels of Tnfrsf18 and Pdcd1 at 15 days after CLP. The increase in TIGIT+ Tregs was accompanied by higher susceptibility to nosocomial bacteria challenge, suggesting their association with post sepsis immunosuppression. Mechanistically, we found that the ST2 deletion abrogated the expansion of the TIGIT+ Treg subset during sepsis. Furthermore, treatment with recombinant IL-33 resulted in the expansion of TIGIT+ Tregs depending on the STAT6 and M2 macrophages. These findings demonstrated that only the TIGIT+ Tregs remain stably expanded at the late phase of sepsis. Moreover, the expansion of TIGIT+ Tregs is dependent on the IL-33/ST2/STAT6/M2 macrophage axis.