The Role of Stress-Induced Activation of HSP70 in Dendritic Cells, CD4+ T Cell, Memory and Adjuvanticity
Inducible HSP70 is the hallmark of cell stress and it may mediate CD4+ T cell memory and adjuvanticity. In vitro interaction between human DC exposed to thermal or oxidative stress and CD4+ T cells elicits homeostatic memory. The mechanism involves activation of the NF-κB signalling pathway that leads to expression of membrane-associated IL-15 molecules. These interact with the IL-15 receptor complex on CD4+ T cells, activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-γ production. CD40 ligand on CD4+ T cells in turn re-activates CD40 molecules on DC. The proliferating CD4+ T cells were characterized as CD45RA−CD62L+ central memory cells. Importantly, the circuit is independent of antigen and MHC class-II interaction with TCR. This was confirmed and extended in vivo studies in BALB/c mice by SC immunization with ovalbumin (OVA) mixed with alum. Furthermore, inflammasomes were elicited, with significant activation of caspase 1, production of IL-1β, and adjuvanticity, demonstrated by enhancing OVA-specific serum IgG antibodies and CD4+ T cell proliferation. The novel finding that alum, the most commonly used adjuvant in vaccines induces HSP70 suggests that stress is involved in the mechanism of adjuvanticity. This was confirmed by inhibition studies with the HSP70 inhibitor PES (phenylethynesulfonamide), which inhibited both inflammasomes and the adjuvant function. Parallel studies were then pursued with oxidative, K+ releasing and a metal ionophore agents. All three stress agents induced HSP70, inflammasomes, interactions between splenic CD11c DC and CD4+ T cells and the adjuvant function. The results suggest that the three stress agents elicit HSP70, inflammasomes, homeostatic memory and adjuvanticity, commensurate with those of alum. These findings extend our understanding of the mechanism of adjuvanticity and may provide an alternative strategy in developing novel adjuvants.
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