title: The PDL1-PD1 axis converts human TH1 cells into regulatory T cells.
abstract: Immune surveillance by T helper type 1 (T(H)1) cells is not only critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GVHD) after transplantation. The inhibitory molecule programmed death ligand 1 (PDL1) has been shown to anergize human T(H)1 cells, but other mechanisms of PDL1-mediated T(H)1 inhibition such as the conversion of T(H)1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause T(H)1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET(+) T(H)1 cells into FOXP3(+) regulatory T (T(reg)) cells in vivo, thereby preventing human-into-mouse xenogeneic GVHD (xGVHD). Either blocking PD1 expression on T(H)1 cells by small interfering RNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized T(H)1 cell differentiation during PDL1 challenge and restored the capacity of T(H)1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human T(H)1 cells to manifest in vivo plasticity, resulting in a T(reg) phenotype that severely impairs cell-mediated immunity. Converting human T(H)1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GVHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection.
authors: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. samarnath@mail.nih.gov
authors: Shoba
authors: S
authors: Amarnath
authors: Courtney W
authors: CW
authors: Mangus
authors: James C M
authors: JC
authors: Wang
authors: Fang
authors: F
authors: Wei
authors: Alice
authors: A
authors: He
authors: Veena
authors: V
authors: Kapoor
authors: Jason E
authors: JE
authors: Foley
authors: Paul R
authors: PR
authors: Massey
authors: Tania C
authors: TC
authors: Felizardo
authors: James L
authors: JL
authors: Riley
authors: Bruce L
authors: BL
authors: Levine
authors: Carl H
authors: CH
authors: June
authors: Jeffrey A
authors: JA
authors: Medin
authors: Daniel H
authors: DH
authors: Fowler
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008070:Lipopolysaccharides; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D050794:STAT1 Transcription Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6