Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner
Identifiers
Identifiers
URI: http://hdl.handle.net/20.500.11940/16739
PMID: 32971928
DOI: 10.3390/ijms21186965
ISSN: 1661-6596
Date issued
2020Journal title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Type of content
Journal Article
DeCS
células TH2 | células TH1 | glicoproteínas de membranas | péptidos y proteínas de señalización intracelular | citocinas | comunicación autocrina | humanos | diferenciación celular | regulación de la expresión génica | células Th17 | semaforinasMeSH
Th2 Cells | Cell Differentiation | Autocrine Communication | Humans | Cytokines | Intracellular Signaling Peptides and Proteins | Th17 Cells | Membrane Glycoproteins | Gene Expression Regulation | Th1 Cells | SemaphorinsAbstract
Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4(+) T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naive Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORgammat in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4(+) T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4(+) T cell-mediated diseases.