Regulatory T Cells Dampen Pulmonary Inflammation and Lung Injury in an Animal Model ofPneumocystisPneumonia

Abstract

CD4+CD25+FoxP3+ regulatory T cells are decreased in patients infected with HIV and have been shown to be critical in mediating Ag tolerance in the lung. Because a subset of Pneumocystis-infected individuals develop substantial lung injury, which can be modeled in immune reconstituted scid mice, we used mouse models of Pneumocystis carinii to investigate the role of regulatory T cells in opportunistic infection and immune reconstitution. In this study, we show that CD4+CD25+FoxP3+ cells are part of the host response to Pneumocystis in CD4+ T cell-intact mice. Moreover, lung injury and proinflammatory Th1 and Th2 cytokine levels in the bronchoalveolar lavage fluid and lung homogenate were increased following CD4+CD25− immune reconstitution in Pneumocystis-infected SCID mice but not in CD4+CD25+ T cell-reconstituted animals. The ability of CD4+CD25+ T cells to control inflammation and injury during the course of Pneumocystis was confirmed by treatment of wild-type C57BL/6 mice with anti-CD25 mAb. These data show that CD4+CD25+ T cells control pulmonary inflammation and lung injury associated with Pneumocystis infection both in the setting of immune reconstitution as well as new acquisition of infection.

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

“…25,26 Compared with WT mice, ␥␦ KO mice had significantly reduced levels of CXCL1, G-CSF, IL-6, and CXCL10 in BAL fluid ( Figure 3C). Of the four cytokines/chemokines observed to be significantly different, CXCL10 was the only one still elevated by 14 days.…”

“…25,26 Bleomycin USP (Hospira Pharmaceuticals Lake Forest, IL) was administered (2-U/kg body weight) in sterile PBS (100 L). Adenovirus encoding CXCL10 or green fluorescent protein (adenovirus control) was administered in 100 L of sterile saline at a concentration of 10 8 plaque-forming units.…”

CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury

“…A subset of CD4 + lymphocytes described as Tregs, expressing the surface marker CD25 (IL-2 receptor α) as well as the transcription factor Forkhead box protein 3 (Foxp3), have been implicated in controlling autoreactive T cells in vivo (11). Recent reports indicate that Tregs exert suppressive effects in an increasing array of pathophysiologic events (12,13), including regulation of immune responses after burn injury in mice (14) and in chronic infections such as pulmonary aspergillosis (15) and Pneumocystis pneumonia (16), and therefore might participate as mediators in ALI or its resolution.…”

Epitope-Specific Regulatory CD4 T Cells Reduce Virus-Induced Illness while Preserving CD8 T-Cell Effector Function at the Site of Infection

“…Detailed immunization and infection procedures were described previously (27). Mice were immunized with RSV M 209-223 or M2 [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] peptide at 100 g/mouse intramuscularly. Peptides were conjugated with keyhole limpet hemocyanin (KLH) by using an Imject immunogen EDC kit (Thermo Fisher Scientific, Inc., Illinois).…”

“…However, the presence of natural regulatory CD4 T cells can have a beneficial effect on immune-mediated pathology, particularly at the site of infection. Tregs have been shown to limit pulmonary inflammation and lung injury induced by pneumocystis infection (29) and to modulate herpes simplex virus-induced inflammatory lesions of the eye (46). Natural Tregs also reduce the symptoms of West Nile virus infections in both humans and mice; Treg-deficient mice were more likely to develop lethal infection (25).…”