Two Phenotypically Distinct Subsets of Spleen Dendritic Cells in Rats Exhibit Different Cytokine Production and T Cell Stimulatory Activity

Abstract

We recently reported that splenic dendritic cells (DC) in rats can be separated into CD4+ and CD4− subsets and that the CD4− subset exhibited a natural cytotoxic activity in vitro against tumor cells. Moreover, a recent report suggests that CD4− DC could have tolerogenic properties in vivo. In this study, we have analyzed the phenotype and in vitro T cell stimulatory activity of freshly isolated splenic DC subsets. Unlike the CD4− subset, CD4+ splenic DC expressed CD5, CD90, and signal regulatory protein α molecules. Both fresh CD4− and CD4+ DC displayed an immature phenotype, although CD4+ cells constitutively expressed moderate levels of CD80. The half-life of the CD4−, but not CD4+ DC in vitro was extremely short but cells could be rescued from death by CD40 ligand, IL-3, or GM-CSF. The CD4− DC produced large amounts of the proinflammatory cytokines IL-12 and TNF-α and induced Th1 responses in allogeneic CD4+ T cells, whereas the CD4+ DC produced low amounts of IL-12 and no TNF-α, but induced Th1 and Th2 responses. As compared with the CD4+ DC that strongly stimulated the proliferation of purified CD8+ T cells, the CD4− DC exhibited a poor CD8+ T cell stimulatory capacity that was substantially increased by CD40 stimulation. Therefore, as previously shown in mice and humans, we have identified the existence of a high IL-12-producing DC subset in the rat that induces Th1 responses. The fact that both the CD4+ and CD4− DC subsets produced low amounts of IFN-α upon viral infection suggests that they are not related to plasmacytoid DC.

Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor

“…DC-sTNFRI induce allospecific tolerance through cytokine production. It is well known that DC influence Th cell differentiation by producing cytokines (42,43). Immature or tolerogenic DCs can drive the differentiation of CD4 ϩ type 1 T-regulatory cells (Tr1) (34,35,44).…”

Intestinal Dendritic Cell Subsets: Differential Effects of Systemic TLR4 Stimulation on Migratory Fate and Activation In Vivo

“…The same two subsets have been identified in rat spleen (17,18), but how these phenotypically similar DC relate functionally is not yet fully clear. In both lymph and spleen, SIRP␣ high DC are more potent than SIRP␣ low DC in the activation of allogeneic CD4 ϩ and CD8 ϩ T cells, naive Ag-specific CD4 ϩ T cells in vivo, and sensitized Ag-specific CD4 ϩ T cells in vitro (6,17,18). In addition, SIRP␣ low lymph DC selectively transport remnants of apoptotic intestinal epithelial cells to the T cell areas (TCAs) of mesenteric LNs (MLN) (7).…”

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

“…Importantly, this phenotypic heterogeneity correlates directly with functional specialization, e.g. uptake of dying cells, secretion of cytokines and skewing of T helper cell differentiation [2][3][4][5]. DC migrating via afferent lymph from peripheral tissues to draining LN both activate naive CD4 + T cells and transduce information that determines the differentiation of the activated cells.…”