Cross-talk between 4-1BB and TLR1-TLR2 Signaling in CD8+ T Cells Regulates TLR2's Costimulatory Effects

• Published in: Cancer immunology research 2016-08, Vol.4 (8), p.708-716
• Main Authors: Joseph, Ann Mary, Srivastava, Ratika, Zabaleta, Jovanny, Davila, Eduardo
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Survival - genetics; Cytotoxicity, Immunologic; Gene Expression; Gene Expression Profiling; Immunomodulation; Melanoma - immunology; Melanoma - metabolism; Melanoma, Experimental; Mice; Mice, Knockout; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Promoter Regions, Genetic; Protein Binding; Signal Transduction; Toll-Like Receptor 1 - metabolism; Toll-Like Receptor 2 - metabolism; Transcription Factors - metabolism; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-15-0173

The activation of TLR-MyD88 (Toll-like receptor-myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1-TLR2-stimulated and unstimulated T-cell receptor transgenic "pmel" and MyD88(-/-) pmel CD8(+) T cells and identified changes in the expression of several TNF family members. In particular, TLR stimulation increased 4-1BB levels in pmel but not in MyD88(-/-)pmel T cells. A link between 4-1BB and TLR1-TLR2 signaling in CD8(+) T cells was highlighted by the suboptimal responses of 4-1BB(-/-) T cells to TLR1-TLR2 agonist, but their normal response to CD28 or OX40 costimulation. Blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1-TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1-TLR2-stimulated cells were not due to increased mRNA stability nor increased histone activation, but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1-TLR2 ligand with an agonistic antibody to 4-1BB enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1-TLR2 signaling in CD8(+) T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. Cancer Immunol Res; 4(8); 708-16. ©2016 AACR.