IL-1 family members induce pro-inflammatory cytokine release in costimulated T cells outside of TCR stimulation (CCR3P.209)

• Published in: The Journal of immunology (1950) Vol. 194; no. 1_Supplement; pp. 49 - 49.10
• Main Authors: Tsurutani, Naomi, St. Rose, Marie-Clare, Mittal, Payal, Adler, Adam, Vella, Anthony
• Format: Journal Article
• Language: English
• Published: 01.05.2015
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.49.10

Abstract Toll-like receptor stimulation induces production of pro-inflammatory cytokines such as IL-1 or IL-12 that act as a 3rd signal in programming antigen-specific effector T cell differentiation. Signal 3, however, can stimulate already differentiated effector T cells to release cytokines such as IFN-g or IL-4. The identity of signal 3 mediators is important to better understand how signal 3 can drive T cell function in the absence of an obvious TCR ligand, which could occur during infection or cancer. We discovered that IL-36 play this role when T cells were co-stimulated with TNF super family members and had differentiated into effectors. By RT-PCR it was found that IL-2 induced IL-36 receptor gene expression and that IL-36 stimulation, in the absence T cell receptor stimulation, released prodigious levels of IFN-g. To understand how signal 3 responses were related to cellular function we used an RNA-POL ChIP-seq approach and found that optimally costimulated T cells were more prone to possess a higher metabolic state. Measurement of glycolysis in these T cells confirmed that they were actively able to consume glucose, but as this activity diminished so did the capacity to respond to IL-36. Thus, the data suggest that T cells can use an “innate” response pathway such as the IL-36R pathway but only when they are undergoing a strong glycolytic response. Therefore, cytokine therapy for effector T cells is possible as long as they are in the correct metabolic state.