In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 3, No. 111 ( 2011-11-30)
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.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.3003130
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2011
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