NF-κB regulates PD-1 expression in macrophages

Alexander P R Bally, Peiyuan Lu, Yan Tang, James W. Austin, Christopher D. Scharer, Rafi Ahmed, Jeremy M. Boss

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Programmed cell death-1 (PD-1) is responsible for T cell exhaustion during chronic viral infections and is expressed on a variety of immune cells following activation. Despite its importance, the mechanisms that regulate PD-1 in cell types other than CD8 T cells are poorly defined. In this study, the molecular mechanisms for inducing PD-1 expression in CD4 T cells, macrophages, and B cells were explored. In CD4 T cells, PD-1 induction following TCR stimulation required NFAT, as the calcineurin/NFAT pathway inhibitor cyclosporin Awas able to block PD-1 induction in a manner similar to that seen in CD8 T cells. In contrast, LPS but not PMA and ionomycin stimulation was able to induce PD-1 expression in macrophages in a manner insensitive to cyclosporin A-mediated inhibition. B cells could use both pathways, although the levels of PD-1 expression were highest with PMA and ionomycin. An NF-κB binding site located upstream of the gene in conserved region C was required for NF-κB-dependent PD-1 gene activation in macrophages. Chromatin immunoprecipitation showed NF-κB p65 binding to this region following stimulation of macrophages with LPS. PD-1 induction was associated with histone modifications characteristic of accessible chromatin; however, in contrast to CD8 T cells, conserved region B in macrophages did not lose CpG methylation upon stimulation and PD-1 expression. The linkage of TLR/NF-κB signaling to the induction of PD-1 suggests the possibility of an opportunistic advantage to microbial infections in manipulating immune inhibitory responses.

Original languageEnglish (US)
Pages (from-to)4545-4554
Number of pages10
JournalJournal of Immunology
Volume194
Issue number9
DOIs
StatePublished - May 1 2015
Externally publishedYes

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Cell Death
Macrophages
T-Lymphocytes
Ionomycin
Cyclosporine
B-Lymphocytes
Histone Code
Calcineurin
Chromatin Immunoprecipitation
Virus Diseases
Methylation
Transcriptional Activation
Chromatin
Binding Sites
Infection
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Bally, A. P. R., Lu, P., Tang, Y., Austin, J. W., Scharer, C. D., Ahmed, R., & Boss, J. M. (2015). NF-κB regulates PD-1 expression in macrophages. Journal of Immunology, 194(9), 4545-4554. https://doi.org/10.4049/jimmunol.1402550

NF-κB regulates PD-1 expression in macrophages. / Bally, Alexander P R; Lu, Peiyuan; Tang, Yan; Austin, James W.; Scharer, Christopher D.; Ahmed, Rafi; Boss, Jeremy M.

In: Journal of Immunology, Vol. 194, No. 9, 01.05.2015, p. 4545-4554.

Research output: Contribution to journalArticle

Bally, APR, Lu, P, Tang, Y, Austin, JW, Scharer, CD, Ahmed, R & Boss, JM 2015, 'NF-κB regulates PD-1 expression in macrophages', Journal of Immunology, vol. 194, no. 9, pp. 4545-4554. https://doi.org/10.4049/jimmunol.1402550
Bally APR, Lu P, Tang Y, Austin JW, Scharer CD, Ahmed R et al. NF-κB regulates PD-1 expression in macrophages. Journal of Immunology. 2015 May 1;194(9):4545-4554. https://doi.org/10.4049/jimmunol.1402550
Bally, Alexander P R ; Lu, Peiyuan ; Tang, Yan ; Austin, James W. ; Scharer, Christopher D. ; Ahmed, Rafi ; Boss, Jeremy M. / NF-κB regulates PD-1 expression in macrophages. In: Journal of Immunology. 2015 ; Vol. 194, No. 9. pp. 4545-4554.
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