Notch2-dependent DC2s mediate splenic germinal center responses

Abstract

CD4⁺ T follicular helper (T_FH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for <i>Notch2</i>-dependent cDC2s, but not <i>Batf3</i>-dependent cDC1s or <i>Klf4</i>-dependent cDC2s, in promoting T_FH and GC B cell formation in response to sheep red blood cells and inactivated <i>Listeria monocytogenes</i> This effect was mediated independent of <i>Il2ra</i> and several <i>Notch2</i>-dependent genes expressed in cDC2s, including <i>Stat4</i> and <i>Havcr2</i> Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation of MHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the <i>Notch2</i>-dependent cDC2 subset in supporting humoral immune responses.