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One important function of conventional dendritic cells (cDC) is their high capacity to capture, process and present Ag to T lymphocytes. Mouse splenic cDC subtypes, including CD8α +  and CD8α −  cDC, are not identical in their Ag presenting and T cell priming functions. Surprisingly, few studies have reported functional differences between CD4 −  and CD4 +  CD8α −  cDC subsets. We show that, when loaded  in vitro  with OVA peptide or whole protein, and in steady-state conditions, splenic CD4 −  and CD4 +  cDC are equivalent in their capacity to prime and direct CD4 +  and CD8 +  T cell differentiation. In contrast, in response to α-galactosylceramide (α-GalCer), CD4 −  and CD4 +  cDC differentially activate invariant Natural Killer T (iNKT) cells, a population of lipid-reactive non-conventional T lymphocytes. Both cDC subsets equally take up α-GalCer  in vitro  and  in vivo  to stimulate the iNKT hybridoma DN32.D3, the activation of which depends solely on TCR triggering. On the other hand, and relative to their CD4 +  counterparts, CD4 −  cDC more efficiently stimulate primary iNKT cells, a phenomenon likely due to differential production of co-factors (including IL-12) by cDC. Our data reveal a novel functional difference between splenic CD4 +  and CD4 −  cDC subsets that may be important in immune responses.

Spleen-Resident CD4+ and CD4− CD8α− Dendritic Cell Subsets Differ in Their Ability to Prime Invariant Natural Killer T Lymphocytes