epsis-Induced Immunosuppression Is Marked by an Expansion of a Highly Suppressive Repertoire of FOXP3(+) T-Regulatory Cells Expressing TIGI

Author(s):Show less -

Fernandes de Lima, Mikhael Haruo ^{[1, 2, 3]} ; Hiroki, Carlos Hiroji ^{[2, 3]} ; Borges, Vanessa de Fatima ^{[1, 3]} ; Martelossi Cebinelli, Guilherme Cesar ^{[2, 3]} ; Santos, Jessica ^{[2, 3]} ; Rosa, Marcos Henrique ^{[1, 2, 3]} ; Silva, Camila Meirelles S. ^{[1, 2, 3]} ; Wanderley, Carlos Wagner S. ^{[1, 3]} ; Goncalves, Augusto Velozo ^{[4, 3]} ; Silva Quirino, Gustavo Fernando ^{[4, 3]} ; Zamboni, Dario S. ^{[4, 3]} ; Cunha, Thiago M. ^{[1, 3]} ; Filho, Jose-Carlos A. ^{[1, 3]} ; Cunha, Fernando Q. ^{[1, 3]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Basic & Appl Immunol, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Ctr Res Inflammatory Dis, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell Biol, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Journal of Infectious Diseases; v. 225, n. 3, p. 531-541, FEB 1 2022.
• Web of Science Citations: 0

Abstract

The routes related to expansion of the T-cell immunoglobulin and ITIM domain (TIGIT)(+) T-regulatory cell repertoire are still unknown. Our study demonstrates that interleukin 33 is pivotal in selectively expanding this repertoire in a STAT6 and M2 macrophage-dependent fashion. Background 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. Methods 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. Results 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. Conclusions 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. (AU)