Inhibition of CD8⁺ T cells and elimination of myeloid cells by CD4⁺ Foxp3⁻ T regulatory type 1 cells in acute respiratory distress syndrome

Abstract

Acute lung injury and acute respiratory distress syndrome (ARDS) are caused by rapid-onset bilateral pulmonary inflammation. We therefore investigated the potential role of interleukin (IL)-10 CD4 Tr1 cells, a regulatory T cell subset with previously identified immunosuppressive functions, in ARDS patients. We first showed that circulating Tr1 cells were upregulated in active and resolved ARDS patients compared to healthy controls and pneumonia patient controls. A significant fraction of these Tr1 cells expressed granzyme B and perforin, while most Tr1 cells did not express interferon gamma (IFN-γ), IL-4, IL-17 or FOXP3, suggesting that the effector functions of these Tr1 cells were primarily mediated by IL-10, granzyme B, and perforin. Indeed, Tr1 cells effectively suppressed CD8 T cell IFN-γ production and induced lysis of monocytes and dendritic cells in vitro. The elimination of myeloid antigen-presenting cells depended on granzyme B production. We also discovered that Tr1 cells could be identified in the bronchoalveolar lavage fluid collected from ARDS patients. All these results suggested that Tr1 cells possessed the capacity to downregulate inflammation in ARDS. In support of this, we found that ARDS patients who resolved the inflammation and survived the syndrome contained significantly higher levels of Tr1 cells than ARDS patients who succumbed to the syndrome. Overall, this report added a novel piece of evidence that ARDS could be intervened by regulatory T cell-mediated suppressive mechanisms.

Scrub Typhus Pathogenesis: Innate Immune Response and Lung Injury During Orientia tsutsugamushi Infection

“…This review highlights what is known regarding vascular activation and the innate immune response during scrub typhus (Figure 1). While adaptive immune cell subsets (CD4 + and CD8 + T cells and Foxp3 + regulatory T cells) are not illustrated in Figure 1, their roles in O. tsutsugamushi infection need to be examined, given their important roles in ARDS development in other infection models (Adamzik et al, 2013; Risso et al, 2015; Li et al, 2016). Murine models of scrub typhus will help dissect key immune components in controlling O. tsutsugamushi infection and host factors and mechanisms underlying cellular injury and ARDS development in severe scrub typhus.…”

Prognostic factors for ARDS: clinical, physiological and atypical immunodeficiency

“…The surviving ARDS patients had significantly higher frequencies of TIM-1+ B cells than did non-survivors, especially CD27+TIM-1+B cells [24]. ARDS patients with resolved inflammation who survived the syndrome had significantly higher levels of Tr1 cells than did ARDS patients who died [25]. In our study, both peripheral blood B-lymphocyte and CD8+T-lymphocyte counts in survivors were significantly higher than those in non-survivors among ARDS patients, and B-lymphocyte and CD8+T-lymphocyte counts were also found to be positively correlated with peripheral blood lymphocyte counts.…”

Prognostic factors for ARDS: clinical, physiological and atypical immunodeficiency

“…The surviving ARDS patients had significantly higher frequencies of TIM-1+ B cells than did non-survivors, especially CD27+TIM-1+B cells [32]. ARDS patients with resolved inflammation who survived the syndrome had significantly higher levels of Tr1 cells than did ARDS patients who died [33]. In our study, both peripheral blood B-lymphocyte and CD8+Tlymphocyte counts in survivors were significantly higher than those in non-survivors among ARDS patients, and B-lymphocyte and CD8+T-lymphocyte counts were also found to be positively correlated with peripheral blood lymphocyte counts.…”

“…Cumulative survival rates at the 28-day follow-up also differed significantly between ARDS patients with different Th17/Treg ratios, and the Th17/Treg imbalance was a potential novel risk indicator in patients with early ARDS [16]. ARDS patients with resolved inflammation who survived the syndrome had significantly higher levels of Tr1 cells than ARDS patients who died [17]. Tfr cells were strongly enriched in ARDS patients, especially in the lung infiltrates, and they may exert critical ameliorating effects in ARDS [18].…”