Effect of RELT on regulation of the threshold of T-cell activation during sterile inflammation.
25 Background: Receptor expressed in lymphoid tissue (RELT) is a type I transmembrane protein, designated TNFRSF19-like, and primarily expressed in lymphoid tissues and immune cells. However, its immunological function has yet to be characterized. Methods: We developed RELT-deficient mice to examine the immunological role of RELT. The RELT–/– mice were exposed to viral and bacterial infection, chemical-induced liver injury, and tumor induction. Results: RELT–/– mice were viable and fertile, and developed normal lymphoid and myeloid cells. RELT transcripts were decreased in T cells and dendritic cells following their activation, and T-cell proliferation was enhanced in the absence of RELT in vitro. Nevertheless, we could not find significant changes in RELT–/– mice infected with virus or bacteria. However, liver injury and inflammation were significantly increased in RELT–/– mice in comparison to RELT+/+ mice after the injection of acetaminophen. Tumor growth rate was also slower in RELT–/– than RELT+/+ mice. Transfer of naïve or activated pmel-1 CD8+ T cells suppressed the growth of B16–F10 tumors and increased host CD8+ tumor-infiltrating cells more efficiently in RELT–/– than in RELT+/+ mice. In particular, naïve pmel-1 CD8+ T cells were present in increased numbers and activated forms in draining lymph nodes of RELT–/– than in RELT+/+ mice, whereas activated pmel-1 CD8+ T cells were not. Conclusions: As RELT–/– mice only showed significant differences in comparison to RELT+/+ mice in pathogen-associated-molecular-pattern-free conditions, these results provide evidence that RELT functions as a negative modulator of T cell responses in a sterile inflammation.