Human Semaphorin-4A drives Th2 responses by binding to receptor ILT-4

• Published in: Nature communications Vol. 9; no. 1; pp. 742 - 11
• Main Authors: Lu, Ning, Li, Ying, Zhang, Zhiqiang, Xing, Junji, Sun, Ying, Yao, Sheng, Chen, Lieping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 13/51; 14/19; 38/61; 631/250/127/1213; 631/250/1619/554/1898/1274; 631/250/256/2515; 631/250/516; Animals; Antigen-presenting cells; Antigen-Presenting Cells - cytology; Asthma; Asthma - metabolism; Binding; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; Cell Differentiation; Cell Line; Cell Proliferation; Cloning; HEK293 Cells; Helper cells; Homology; Human behavior; Humanities and Social Sciences; Humans; Immune response; Immunoglobulins; Lung - metabolism; Lungs; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mucin; multidisciplinary; Oligonucleotide Array Sequence Analysis; Pathogenesis; Receptors, Antigen, T-Cell - metabolism; Receptors, Immunologic - physiology; Science; Science (multidisciplinary); Semaphorins - physiology; T cell receptors; Th2 Cells - cytology; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03128-9

Semaphorin-4A (Sema4A) has been implicated in the co-stimulation of T cells and drives Th1 immune responses by binding to the receptor T-cell immunoglobulin and mucin domain protein 2 (Tim-2) in mice. Here we show that human, but not murine, Sema4A is preferentially expressed on antigen-presenting cells, and co-stimulates CD4 + T-cell proliferation and drives Th2 responses. By employing two independent cloning strategies, we demonstrate that Immunoglobulin-like transcript 4 (ILT-4) is a receptor for human SEMA4A (hSEMA4A) on activated CD4 + T cells. We also find hSEMA4A to be highly expressed in human asthmatic lung tissue, implying its potential function in disease pathogenesis. Our study defines a different biological function of hSEMA4A from its murine homolog through its binding to the receptor of ILT-4 to co-stimulate CD4 + T cells and regulate Th2 cells differentiation. Semaphorin-4A is a cell surface protein with known functions in neural development and immune regulation, but the mechanism for immune modulation is unclear. Here the authors show that ILT-4, previously found on myeloid cells, is the receptor of Semaphorin-4A on activate human CD4 T cells for mediating T cell co-stimulation.