The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation

Abstract

Dendritic cell (DC) maturation is an innate response that leads to adaptive immunity to coadministered proteins. To begin to identify underlying mechanisms in intact lymphoid tissues, we studied α-galactosylceramide. This glycolipid activates innate Vα14+ natural killer T cell (NKT) lymphocytes, which drive DC maturation and T cell responses to ovalbumin antigen. Hours after giving glycolipid i.v., tumor necrosis factor (TNF)–α and interferon (IFN)-γ were released primarily by DCs. These cytokines induced rapid surface remodeling of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs from CD40−/− and CD40L−/− mice did not elicit CD4+ and CD8+ T cell immunity, even though the DCs exhibited presented ovalbumin on major histocompatibility complex class I and II products and expressed high levels of CD80/86. Likewise, an injection of TNF-α up-regulated CD80/86 on DCs, but CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12 production, but IL-12p40−/− mice generated normal ovalbumin-specific responses. Therefore, the link between innate and adaptive immunity via splenic DCs and innate NKT cells has several components under distinct controls: antigen presentation in the steady state, increases in costimulatory molecules dependent on inflammatory cytokines, and a distinct CD40/CD40L signal that functions together with antigen presentation (“signal one”) and costimulation (“signal two”) to generate functioning CD4+ T helper cell 1 and CD8+ cytolytic T lymphocytes.

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

“…35 It is known that maturation of DCs is associated with increased expression of MHC class II and co-stimulatory molecules, such as CD40, CD80 and CD86 on the cell surface, 36 and that interaction of CD40 and CD40L is essential for the differentiation of DCs from immature into fully mature phenotype that are able to prime adaptive T cell responses. 37 In agreement with these reports, our results showed that RT/IL-12 treatment greatly increased the levels of MHC class II and co-stimulatory molecules CD40 and CD86 on DCs (Figure 5), suggesting that these DCs may gain antigen-presentation functions to promote antitumor T cell responses.…”

C‐reactive protein impairs human CD14+ monocyte‐derived dendritic cell differentiation, maturation and function

“…Since MLR activity in CRP-treated DC was even lower than that of normal iDC, CRP may continuously exert its inhibitory action on DC; normal iDC could undergo additional maturation during the MLR assay, while CRPtreated DC could not. In addition, it has been suggested that stimulation of MLR by mDC also requires CD40 and CD40L interaction [53]; therefore, down-regulation of CD40 on CRP-treated DC could also play an important role in the impairment of DC function.…”

Dendritic cells: Understanding immunogenicity

“…using the hybrid antibodies or dying cells, antigen presentation took place but the corresponding T cells were deleted. When a stimulus for DC maturation was coadministered with the targeted antigen, clonal expansion was accompanied by differentiation to high levels of IFN-c production [70,71,75]. As a result, we proposed that DC could control both immunity and tolerance.…”

“…signal one (peptide-MHC) and signal two (B7 costimulators), is insufficient to explain immunogenicity, because DC are competent in both and can still require additional functions, e.g. through CD40 signals [75]. Recently, it was found that the up-regulation of CD70 was essential for one subset of DEC-205 + DC to induce the Th1 pathway of CD4 + T cell differentiation [90].…”