title: The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4+T cells.
abstract: Programmed cell death 1 ligand 1 (PD-L1) is an important regulator of T-cell responses and may consequently limit anticancer immunity. We have recently identified PD-L1-specific, cytotoxic CD8+T cells. In the present study, we develop these findings and report that CD4+helper T cells spontaneously recognize PD-L1. We examined the locality of a previously identified HLA-A*0201-restricted PD-L1-epitope for the presence of possible CD4+T-cell epitopes. Thus, we identified naturally occurring PD-L1-specific CD4+T cells among the peripheral blood lymphocytes of cancer patients and - to lesser extents - healthy donors, by means of ELISPOT assays. PD-L1-specific CD4+T cells appeared to be TH17 cells exhibiting an effector T-cell cytokine profile. Hence, PD-L1-specific CD4+T cells released interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-17 (IL-17) in response to a long PD-L1-derived peptide. Furthermore, we demonstrate that the specific recognition of PD-L1 by CD4+T cells is MHC class II-restricted. Natural T-cell responses against PD-L1 are noteworthy as they may play a prominent role in the regulation of the immune system. Thus, cytokine release from PD-L1-specific CD4+T cells may surmount the overall immunosuppressive actions of this immune checkpoint regulator. Moreover, PD-L1-specific T cells might be useful for anticancer immunotherapy, as they may counteract common mechanisms of immune escape mediated by the PD-L1/PD-1 pathway.
authors.affiliation: 1Center for Cancer Immune Therapy (CCIT); Department of Hematology and Oncology; Copenhagen University Hospital; Herlev, Denmark.
authors.forename: Shamaila
authors.initials: S
authors.lastname: Munir
authors.forename: Gitte Holmen
authors.initials: GH
authors.lastname: Andersen
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
keywords: CD4; PD-L1; Th17; antigen; autoimmunity