Tim-3 Regulates Tregs' Ability to Resolve the Inflammation and Proliferation of Acute Lung Injury by Modulating Macrophages Polarization.

We recently reported that CD4thornCD25thorn regulatory Tcells (Tregs) contributed to the recovery of patients with acute lung injury (ALI) by upregulating T cell immunoglobulin and mucin-domain containing-3 (Tim-3). However, the molecular mechanism by which Tim-3 regulates Tregs' function in the resolution and fibroproliferation after ALI remains unknown. In this study, we adoptively transferred Tim-3thornTregs or Tim-3(-)Tregs into lipopolysaccharide -induced ALI mice model. Data demonstrated that Tim-3+Tregs not only decreased indices of lung inflammation and injury but also mitigated lung fibrosis after ALI. Furthermore, we observed that the transfer of Tim-3+Tregs led to M2-like macrophage differentiation as demonstrated by significantly upregulated levels of M2-associated phenotypic markers as well as downregulated expressions of M1-related markers in both the profibrotic lung tissue and sorted pulmonary monocytes after ALI. In addition, cytokines such as interleukin (IL)-10 and IL-4 were also upregulated in lung tissues after Tim-3+Tregs transferring. In vitro experiments further demonstrated that cell-contact cocultures with Tregs lacking Tim-3 presented decreased polarization of M2-like macrophages partially mediated by a decreased expression and function of STAT-3. Therefore, these data demonstrate a previously unrecognized function of Tim-3 on Tregs in their ability to repress the fibroproliferation of ALI by inducing alternative macrophages polarization. Moreover, the data highlight that Tim-3+Tregs-mediated induction of M2like macrophages may be a novel treatment modality with transitional potential.