LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites

MicroRNAs (miRNAs) have been shown as an important regulator in the pathologies of acute lung injury (ALI). However, the potential effect of miRNA-based therapeutic studies in ALI remains poorly understood. We assessed the effect of antisense oligonucleotides (ASOs) against miR-155 on the development of ALI using a murine ALI model. We found that miR-155 ASO treatment could enhance the recovery of ALI as evidenced by accelerated body weight back, reduced level of bronchoalveolar lavage (BAL) protein and proinflammatory cytokines, and reduced number of BAL cells. Adoptive cell transfer assay in RAG1−/− mice showed that CD4+CD25+ regulatory T cells (Tregs) mediated the enhanced recovery of ALI. Mechanistic evidence showed that enhanced expansion of Tregs in vivo, dominantly induced by IL-10–secreting M2-like macrophages, was critical for their elevated proportion in miR-155 ASO-treated ALI mice. Finally, we report that C/EBPβ, a target molecule of miR-155, was upregulated and associated with IL-10 secretion and M2-like phenotype of macrophages. These data provided a previously unknown mechanism for miRNA-based therapy against ALI, which could ultimately aid the understanding of recovery of ALI and the development of new therapeutic strategies against clinical inflammatory lung disease.

Section: Cd4supporting

confidence: 52%

Section: The Expansion Of Tregs In Mir-155 Aso-treated Ali Micementioning

confidence: 92%

Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

Guo

Wen

Qin

et al. 2013

“…Plasmodium infection induced T cell exhaustion, which could be restored by the blockade of PD ligand 1 (PD-L1) and LAG-3 in vivo; blocking PD-L1 and LAG-3 restored CD4 + T cell function, amplified the numbers of follicular helper T cells, enhanced protective Abs, and rapidly cleared the established bloodstage Plasmodium infection in mice (25). LAG-3 also defines an active CD4 + CD25 high Foxp3 + regulatory T cell subset, the fre-quency of which is enhanced in the PBMCs of cancer patients (26). There is increasing evidence of the role of LAG-3 and its involvement in regulatory T cell functions (27,28).…”

mentioning

confidence: 99%

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

Tian

Zhang

Qiu

et al. 2015

112

110

T cells develop functional defects during HIV-1 infection, partially due to the upregulation of inhibitory receptors such as programmed death-1 (PD-1) and CTLA-4. However, the role of lymphocyte activation gene-3 (LAG-3; CD223), also known as an inhibitory receptor, in HIV infection remains to be determined. In this study, we revealed that LAG-3 on T cells delivers an inhibitory signal to downregulate T cell functionality, thereby playing an immunoregulatory role during persistent HIV-1 infection. We observed that HIV-1 infection results in a significant increase in LAG-3 expression in both the peripheral blood and the lymph nodes. The upregulation of LAG-3 is dramatically manifested on both CD4+ and CD8+ T cells and is correlated with disease progression. As expected, prolonged antiretroviral therapy reduces the expression of LAG-3 on both CD4+ and CD8+ T cells. The ex vivo blockade of LAG-3 significantly augments HIV-specific CD4+ and CD8+ T cell responses, whereas the overexpression of LAG-3 in T cells or the stimulation of LAG-3 on T cells leads to the reduction of T cell responses. Furthermore, most LAG-3 and PD-1 are expressed in different T cell subsets. Taken together, these data demonstrate that the LAG-3/MHC class II pathway plays an immunoregulatory role, thereby providing an important target for enhancing immune reconstitution in HIV-infected patients. Additionally, the LAG-3/MHC class II pathway may synergize with PD-1/PD ligand to enhance T cell–mediated immune responses.

“…There is also increasing evidence of its involvement in regulatory function of tumor-infiltrated T cells in cancer, such as in Hodgkin's lymphomas (24) and in prostate cancer (25). Recently, LAG-3 expression also defined an active CD4 + CD25 high FOXP3 + Treg subset, which is endowed with potent suppressor activity that requires cell-to-cell contact and is found at enhanced frequency in PBMCs of patients with melanoma and is expanded at tumor sites (26). As a soluble fusion protein, LAG-3 has also been shown to bind MHC II with a much higher avidity than CD4 (27), to increase the capacity of MHC II-positive macrophages and immature dendritic cells to induce T cell responses in vitro (28), and to enhance the in vitro induction of viral and tumor-specific cytotoxic T cells (29).…”

mentioning

confidence: 99%

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

Hémon

Jean-Louis

Ramgolam

et al. 2011

Self Cite

200

146

Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3–transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3–induced protection from apoptosis. Altogether, our data suggest that the LAG-3–MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3–MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.