Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memory.
Evidence is presented that thermal or oxidizing stress-activated DC interact with CD4(+) T cells to induce and maintain a TCR-independent homeostatic memory circuit. Stress-activated DC expressed endogenous intra-cellular and cell surface HSP70. The NF-kappaB 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(+) T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-gamma production. CD40 ligand on CD4(+) 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(+) T cells were characterized as CD45RA(-) CD62L(+) 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(+) T-cell interacting circuit, which may be responsible for maintaining a homeostatic antigen-independent memory.
Wang
Yufei
Y
Mucosal Immunology Unit, Kings College London, Guy's Hospital, London, UK.
Seidl
Thomas
T
Whittall
Trevor
T
Babaahmady
Kaboutar
K
Lehner
Thomas
T
D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D053647:Receptors, Interleukin-15 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013312:Stress, Physiological / Q000276:immunology*
D019013:CD40 Antigens; D018840:HSP70 Heat-Shock Proteins; D019409:Interleukin-15; D016328:NF-kappa B; D053647:Receptors, Interleukin-15; D023201:CD40 Ligand; D007371:Interferon-gamma