Leavenworth, JianmeiVerbinnen, BertYin, JieHuang, HuicongCantor, Harvey2015-08-032014Leavenworth, Jianmei W., Bert Verbinnen, Jie Yin, Huicong Huang, and Harvey Cantor. 2014. “A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells.” Nature immunology 16 (1): 96-106. doi:10.1038/ni.3050. http://dx.doi.org/10.1038/ni.3050.1529-2908http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820893Follicular helper T (TFH) cells and follicular regulatory T (TFR) cells regulate the quantity and quality of humoral immunity. Although both cell types highly express the co-stimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that ICOS activation in CD4+ T cells promotes the interaction of the p85α regulatory subunit of the signaling kinase PI3K and intracellular osteopontin (OPN-i), followed by nuclear translocation of OPN-i, interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 expression by OPN-i is essential for sustained TFH and TFR cell responses and regulation of the germinal center B cell response to antigen. As such, the p85α–OPN-i axis represents a molecular bridge that couples ICOS activation to Bcl-6-dependent functional differentiation of TFH and TFR cells and suggests new therapeutic avenues to manipulate their responses.en-USJournal Article2015-08-0310.1038/ni.3050