No abstract

Natural killer (NK) cells play pivotal roles in innate immunity as well as in anti-tumor responses via natural killing, while their activity is tightly regulated by cell-surface inhibitory receptors. Immunoglobulin (Ig)-like transcript 3/leukocyte Ig-like receptor B4 (ILT3/LILRB4, also known as gp49B in mice) is an inhibitory receptor expressed on activated NK cells as well as myeloid-lineage cells. The common physiologic ligand of human LILRB4 and gp49B is identified very recently as fibronectin (FN), particularly the N-terminal 30 kDa domain (FN30). We hypothesized that LILRB4 could bind FN on target cells in trans together with integrin, a classical FN receptor, in cis and deliver an inhibitory signal in NK cells, leading to attenuated natural killing. Flow cytometric and confocal microscopic analyses of NK cell-surface gp49B and integrin suggested that these novel and classical FN receptors, respectively, co-engage FN immobilized on a culture plate. Biochemical analyses indicated that tyrosine phosphorylation of spleen tyrosine kinase was augmented in gp49B-deficient NK cells upon binding to the immobilized FN. While surface FN-poor YAC-1 cells were evenly sensitive as to natural killing of both gp49B-positive and -negative NK cells, the killing of FN-rich Lewis lung carcinoma cells, but not the FN30-knockout cells, was augmented among gp49B-deficient NK cells. These results suggest that the natural cytotoxicity of NK cells is negatively regulated through LILRB4/gp49B sensing FN on target cells, which sheds light on the unexpected role of LILRB4 and FN as a potential attenuator of NK cell cytotoxicity in the tumor microenvironment.

The International Phonetic Alphabet (IPA) is the most commonly used set of phonetic symbols but it can be difficult to understand and too abstract for non-phoneticians, such as English learners and foreign language educators. One of the factors that makes it difficult for English learners is the number of vowels used in English. In previous research, this problem was solved by proposing a condensed list of 13 English vowels and 24 consonants that are logically organized for North American English, and by assigning a new phonetic symbol font called Sound Spelling to these phonemes. However, there are currently no English texts that have Sound Spelling to show learners this easy way to pronounce and it is difficult for non-phoneticians to write transcriptions right away, because materials using those symbols are lacking for English learners. In this research, we developed a web application, now publicly available, that converts input English into Sound Spelling quickly and accurately to solve this problem.