Programmed Death-1 Antibody Blocks Therapeutic Effects of T-Regulatory Cells in Cockroach Antigen-Induced Allergic Asthma

Abstract

We recently reported that the adoptive transfer of T-regulatory cells (Tregs) isolated from lung and spleen tissue of green fluorescent protein-transgenic mice reversed airway hyperresponsiveness and airway inflammation. Because Programmed Death-1 (PD-1) is a pivotal receptor regulating effector T-cell activation by Tregs, we evaluated whether PD-1 is involved in the therapeutic effect of naturally occurring Tregs (NTregs) and inducible Tregs (iTregs) in cockroach (CRA)-sensitized and challenged mice. The CD4 1 CD25 1 NTregs and CD4 1 CD25 2 iTregs isolated from the lungs and spleens of BALB/c mice were adoptively transferred into CRA-sensitized and CRA-challenged mice with and without anti-PD-1 antibody (100 mg/ mice). The CD4 1 CD25 1 T cells in the lung were phenotyped after adoptive transfer. Concentrations of IL-4, IL-5, IL-10, IFN-g, and IL-13 in bronchoalveolar lavage fluid (BALF) were measured using ELISA. The NTregs and iTregs from either lung or spleen tissue reversed airway hyperresponsiveness for at least 4 wk. However, the therapeutic effect was blocked by administering the anti-PD-1 antibody. The administration of Tregs-recipient mice with anti-PD-1 antibody significantly decreased cytotoxic T-lymphocyte antigen-4 expression, with low concentrations of Forkhead-winged transcriptional factor box 3 (Foxp3) mRNA transcripts in lung CD4 1 CD25 1 T cells. These mice had substantially higher concentrations of BALF IL-4, IL-5, and IL-13, but significantly decreased levels of BALF IL-10. Adoptive therapy recipients without the anti-PD-1 antibody exhibited high levels of CTLA-4 expression and Foxp3 transcripts in lung CD4 1 CD25 1 T cells, with a significant decrease in BALF IL-4, IL-5, and IL-13 concentrations and a substantial increase in BALF IL-10 concentrations. These data suggest that the reversal of airway hyperresponsiveness and airway inflammation by Tregs is mediated in part by PD-1, because other costimulatory molecules (e.g., inducible costimulatory molecule [ICOS] or CTLA-4) have been shown to play a role in Treg-mediated suppression.

Both PD-1 Ligands Protect the Kidney from Ischemia Reperfusion Injury

“…On the other hand, stimulating PD-1 on Tregs may enhance their anti-inflammatory properties in a currently unknown way. In support of this, we and several other laboratories have found that PD-1 KO Tregs or Tregs in the presence of antibodies that interfere with PD-1 signaling do not suppress inflammation (19, 25, 28, 31, 32). Another possibility is reverse signaling, whereby Tregs (and other cells that express PD-1) could send anti-inflammatory signals into immune cells that express the PD-1 ligands as reported previously (66) or pro-survival signals through PD-1/PD-L1 interaction into PD-L1 expressing cells such as tubular epithelial cells (60).…”

“…PD-1 stimulation leads to inhibition of TCR signaling in CD4+ and CD8+ T cells (29, 30). Nonetheless, PD-1 is indispensable for Treg function, as recent studies show that Tregs lacking PD-1, or Tregs in the presence of PD-1 blocking antibodies, display impaired suppressive activity in vitro and in vivo (19, 25, 28, 31, 32). …”

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T Cells and Th17 Cells

“…In addition to Foxp3, molecules associated with Treg development were upregulated by AG490 treatment. ICOS and PD-1 are required for the development of Tregs and their regulation of effector T cells (40,41). ICAM-1 is associated with TGF-b-induced Foxp3 expression (42), and CD103 has been used as a marker of in vivoactivated CD4 +…”

Clinical view on the importance of dendritic cells in asthma

“…A group from Germany recently showed that the expression of PD-L1 is regulated by TLR/p38/MAPK/STAT3 pathway in DCs to modulate cytokines for the development of tolerogenic DCs [120]. Our group has demonstrated that Flt3 ligand treatment in OVA-sensitized and challenged mice increases PD-L1 and PD-L2 expression levels in CD11c high , CD11b low DCs [123]. The positive correlation of Flt3 treatment with PD-L2 expression might be responsible for decrease in T-lymphocyte proliferation.…”

“…Targeting PD-L2 on DCs, which directly reduces the IL-12p40 production on allergen exposure, could modulate IL-13, and thereby help in ameliorating the DC-driven allergic response [138]. By adoptive transfer of naturally occurring Tregs (CD4 + CD25 + ) and inducible Tregs (CD4 + CD25 − ) isolated from lungs and spleen of BALB/c mice into cockroach antigen-sensitized and challenged mice, we found that program death-1 (PD-1) regulates AHR and airway inflammation, and thus could be a target for therapeutic intervention [123]. Gamma-interferon-inducible lysosomal thiol reductase (GILT) reduces disulfide bonds in proteins taken up by DCs for optimal processing and presentation on MHC class II molecules.…”