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High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.

ABSTRACT: The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation,which led us to investigate the etiology of belatacept–resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectively enable protection against diverse classes of pathogens and can cross-react with allogeneicantigen and mediate graft rejection. T helper 17(Th17) cells are a pro-inflammatory CD4+ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1)and Th17 memory compartments contained a similar frequency of divided cells following allogeneic stimulation.Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of the coinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses but augmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renal transplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevated frequency of Th17 memory cells was associated with acute rejection during belatacept therapy. These data highlight important differences in costimulatory and coinhibitory requirements of CD4+ memory subsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications for immunomodulation strategies.

SUBMITTER: Krummey SM

PROVIDER: S-EPMC4124942 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.

Krummey S M SM Cheeseman J A JA Conger J A JA Jang P S PS Mehta A K AK Kirk A D AD Larsen C P CP Ford M L ML

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20140301 3

The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation,which led us to investigate the etiology of belatacept–resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectively enable protection against diverse classes of pathogens and can cross-react with allogeneicantigen and mediate g ...[more]

PMID: 24730049

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Project description:BackgroundTransforming growth factor (TGF)-? plays a dual role during mammary gland development and tumorigenesis and has been shown to stimulate epithelial-mesenchymal transition (EMT) as well as cellular migration. The Wnt/?-catenin pathway is also implicated in EMT and inappropriate activation of the Wnt/?-catenin signaling pathway leads to the development of several human cancers, including breast cancer. Secreted frizzled-related protein 1 (SFRP1) antagonizes this pathway and loss of SFRP1 expression is frequently observed in breast tumors and breast cancer cell lines. We previously showed that when SFRP1 is knocked down in immortalized non-malignant mammary epithelial cells, the cells (TERT-siSFRP1) acquire characteristics associated with breast tumor initiating cells. The phenotypic and genotypic changes that occur in response to SFRP1 loss are consistent with EMT, including a substantial increase in the expression of ZEB2. Considering that ZEB2 has been shown to interact with mediators of TGF-? signaling, we sought to determine whether TGF-? signaling is altered in TERT-siSFRP1 cells.MethodsLuciferase reporter assays and real-time PCR analysis were employed to measure TGF-? transcriptional targets. Western blot analysis was used to evaluate TGF-?-mediated ERK1/2 phosphorylation. Migration chamber assays were utilized to quantify cellular migration. TERT-siSFRP1 cells were transfected with Stealth RNAi™ siRNA in order to knock-down the expression of ZEB2.ResultsTERT-siSFRP1 cells exhibit a significant increase in both TGF-?-mediated luciferase activity as well as TGF-? transcriptional targets, including Integrin ?3 and PAI-1. Phosphorylation of ERK1/2 is increased in TERT-siSFRP1 cells in response to enhanced TGF-? signaling. Furthermore, when the TGF-? pathway is blocked with a TGF-?R antagonist (LY364947), cellular migration is significantly hindered. Finally, we found that when ZEB2 is knocked-down, there is a significant reduction in the expression of exogeneous and endogenous TGF-? transcriptional targets and cellular migration is impeded.ConclusionsWe demonstrate that down-regulation of SFRP1 renders mammary epithelial cells more sensitive to TGF-? signaling which can be partially ameliorated by blocking the expression of ZEB2.

Dataset Information

High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.

Publications

High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.

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