CD4 Expression on Splenic DCs Coordinates their Positioning in a Cell-Intrinsic Manner and is Necessary for Optimal CD4+ T cell Activation

Abstract

Abstract The immunological dogma of MHC-class restriction states helper T cells expressing the co-receptor CD4 perceive antigen in the context of MHC-class II while cytotoxic CD8+ T cells recognize antigen presented on MHC-class I. Paradoxically, dendritic cells (DCs) which express high levels of MHC molecules (yet lack recombined antigen receptors) differentially express CD4 and CD8α, which have classically been used to subset DC populations within secondary lymphoid tissues. Why DCs concurrently express MHC molecules and T cell co-receptors has puzzled immunologists since their discovery on DCs in the mid 1990’s. However, studying the function of these molecules on DCs is confounded by the fact that their T cell counterparts are absent in CD4 or CD8α-deficient mice. Here using a mixed chimera system in which CD4 deficiency can be restricted specifically within the DC compartment, we show CD4-expression on DCs is necessary to drive optimal antigen-specific CD4+ T cell proliferation in vivo. Impaired T cell proliferation which occurs when DCs lack CD4 appears to result from their inability to efficiently access the T cell follicle. Therefore, DC-intrinsic CD4 expression coordinates the micro-anatomical positioning of DCs within the spleen and is necessary for optimal CD4+ T cell activation.