Stress‐activated dendritic cells interact with CD4⁺ T cells to elicit homeostatic memory

Abstract

Evidence is presented that thermal or oxidizing stress-activated DC interact with CD41 T cells to induce and maintain a TCR-independent homeostatic memory circuit.Stress-activated DC expressed endogenous intra-cellular and cell surface HSP70. The NFjB signalling pathway was activated and led to the expression of membrane-associated IL-15 molecules. These interacted with the IL-15 receptor complex on CD4 1 T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-c production. CD40 ligand on CD4 1 T cells in turn re-activated CD40 molecules on DC, inducing DC maturation and IL-15 expression thereby maintaining the feedback circuit. The proliferating CD4 1 T cells were characterized as CD45RA À CD62L 1 central memory cells, which underwent homeostatic proliferation. The circuit is independent of antigen and MHC-class-II-TCR interaction as demonstrated by resistance to TCR inhibition by ZAP70 inhibitor or MHC-class II antibodies. These findings suggest that stress can activate a DC-CD4 1 T-cell interacting circuit, which may be responsible for maintaining a homeostatic antigen-independent memory.

Stress for maintaining memory: HSP70 as a mobile messenger for innate and adaptive immunity

“…The findings that HSP70 binds various components of pathogens (such as LPS, flagellin and other lipid-based TLR ligands) and the contamination of nucleotides ATP/ADP during the preparation of HSP70 by several groups warrant a cautious interpretation of previous data regarding the in vitro effects of HSP70 on APC [3]. In the current study, Wang et al [14] use endogenous autologous HSP70, i.e. HSP70 expressed by DC after stress, which avoids pathogen contaminations and thus suggests a role of HSP70 in activating DC.…”

“…In this regard, cell surface HSP70 can be viewed as a membranebound cytokine or membrane ligands that could bind with and be recognized by HSP70 receptors, and facilitates APC-T cell interactions. In this issue of European Journal of Immunology, Wang et al [14] show that HSP70 is mobilized to the cell surface of DC by stress, which leads to NF-kB-dependent upregulation of membrane-bound IL-15, which in turn, activates the CD4 1 CD45RA memory T cells. More importantly, the study suggests that HSP70 expressed by ''stressed'' DC can regulate the interaction between DC and T cells via indirect regulation of T-cell CD40L expression.…”

“…This stress-induced proliferation of memory T cells is of physiological significance, given that fever (or slight elevation of body temperature) is a common response of the body to usual stimuli such as various slight infections and exercise. In the study [14], the authors perform extensive experiments with the following major observations: (i) thermal-stressed DC promote the proliferation, CD40L expression and IFN-g production of CD4 induce the maturation and IL-12p40 production of DC. They [14] finally conclude that stressed DC may be involved in the maintenance of antigen-independent memory by activating a DC-T cells circuit via cell surface HSP70-induced upregulation of membrane-bound IL-15.…”

“…In the study [14], the authors perform extensive experiments with the following major observations: (i) thermal-stressed DC promote the proliferation, CD40L expression and IFN-g production of CD4 induce the maturation and IL-12p40 production of DC. They [14] finally conclude that stressed DC may be involved in the maintenance of antigen-independent memory by activating a DC-T cells circuit via cell surface HSP70-induced upregulation of membrane-bound IL-15. The central finding of the study is that stressed DC can upregulate membrane-bound IL-15 -this is a critical finding, given that IL-15 is essential for the induction and maintenance of memory T cells [15]; however, several key concerns of immunologists should be further addressed for the mechanisms involved in the process.…”

Heat stress upregulation of Toll-like receptors 2/4 and acute inflammatory cytokines in peripheral blood mononuclear cell (PBMC) of Bama miniature pigs: an in vivo and in vitro study

“…Heat stress or oxidative stress upregulates the expression of IL-15 via the activation of NF-κB (Wang et al, 2010). In pigs under transportation stress, serum concentrations of IL-2, IL-6 and IL-10 were highest at 1 h, whereas concentrations of IL-6 and IL-10 were significantly decreased at 4 h (Lv et al, 2011).…”