The Syk–NFAT–IL-2 Pathway in Dendritic Cells Is Required for Optimal Sterile Immunity Elicited by Alum Adjuvants

Abstract

Despite a long history and extensive usage of insoluble aluminum salts (alum) as vaccine adjuvants, the molecular mechanisms underpinning Ag-specific immunity upon vaccination remain unclear. Dendritic cells (DCs) are crucial initiators of immune responses, but little is known about the molecular pathways used by DCs to sense alum and, in turn, activate T and B cells. In this article, we show that alum adjuvanticity requires IL-2 specifically released by DCs, even when T cell secretion of IL-2 is intact. We demonstrate that alum, as well as other sterile particulates, such as uric acid crystals, induces DCs to produce IL-2 following initiation of actin-mediated phagocytosis that leads to Src and Syk kinase activation, Ca 2+ mobilization, and calcineurin-dependent activation of NFAT, the master transcription factor regulating IL-2 expression. Using chimeric mice, we show that DC-derived IL-2 is required for maximal Ag-specific proliferation of CD4 + T cells and optimal humoral responses following alum-adjuvanted immunization. These data identify DC-derived IL-2 as a key mediator of alum adjuvanticity in vivo and the Src-Syk pathway as a potential leverage point in the rational design of novel adjuvants.

CD83 orchestrates immunity toward self and non-self in dendritic cells

“…In contrast to IL-2, we detected no differences in the expression of immunomodulatory molecules, such as TGF-β or indoleamine-2,3-dioxygenase 1, in CD83-deficient DCs after stimulation with TLR-Ls or LPS, respectively (Supplemental Figure 2F). In T cells, IL-2 expression is controlled by the transcription factor Nfatc2, and this pathway is described in DCs as an important route for T cell stimulation (32). Thus, we were interested in whether Nfatc2 signaling in BDMCs was modified in CD83 ΔDC in comparison with control animals.…”

Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want

“…Inhibition of IL-2 expression specifically in dendritic cells reduced the antibody response to aluminum-adjuvanted vaccines. 123 However, the mouse immunization experiments in this report were carried out with Imject TM Alum, and the role of NFAT and DC-secreted IL-2 in the immune response to vaccines formulated with AH and AP adjuvants remains to be determined.…”

Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

“… 112) Flow cytometric analysis on tumor infiltrating lymphocytes showed that, in patients with GBM, the expression of immune checkpoint molecules like PD-1 and CTLA-4 were significantly higher than that in T-cells from peripheral blood mononuclear cells (PBMCs). 113) Glioma cells evade immune surveillance by expressing PD-1, CTLA-4, and other immune checkpoint molecules that negatively regulate cytotoxic T-lymphocytes (CTL) 114 , 115) (109, 110) and activate regulatory T-cells (Treg), which suppresses effector T-cells. 112) Collectively, PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, called immune checkpoint inhibitors, have been developed for several cancers, including GBMs.…”