Cross-talk between 4-1BB and TLR1-TLR2 Signaling in CD8+ T Cells Regulates TLR2's Costimulatory Effects.
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.
University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland. Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland.
Ann Mary
AM
Joseph
University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland.
Ratika
R
Srivastava
Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
Jovanny
J
Zabaleta
University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland. Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland. edavila@som.umaryland.edu.
Eduardo
E
Davila
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D020869:Gene Expression Profiling; D056747:Immunomodulation; D008545:Melanoma / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D053594:Myeloid Differentiation Factor 88; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D014157:Transcription Factors; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha