CD40 Is a Cellular Receptor Mediating Mycobacterial Heat Shock Protein 70 Stimulation of CC-Chemokines

Wang, Yufei; Kelly, Charles; Karttunen, Jaana T.; Whittall, Trevor; Lehner, Paul J.; Duncan, Lidia M.; MacAry, Paul A.; Younson, Justine; Singh, Mahavir; Oehlmann, Wulf; Cheng, Genhong; Bergmeier, Lesley A.; Lehner, Thomas

doi:10.1016/s1074-7613(01)00242-4

Cited by 244 publications

(215 citation statements)

References 51 publications

(2 reference statements)

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“…This would enable DC migration from the skin to the draining LN [23], and subsequently T cell priming in CD154 -/-but not CD40 -/-mice. The 70-kDa mycobacterial heat shock protein, present in CFA and able to bind CD40 [26], would be a candidate. Although this is an interesting possibility, our primary interests in this study lay in elucidating the effects of anti-CD40 versus anti-OX40 upon tolerance induction.…”

Section: Resultsmentioning

confidence: 99%

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

2006

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An adjuvant can be defined as an agent that non‐specifically promotes the immune response to an accompanying antigen. Ligation of CD40 on the surface of the antigen‐presenting cell leads to upregulation of OX40 ligand which, in turn, ligates OX40 on the activated T cell resulting in prolonged T cell proliferation/survival, boosting the immune response. Thus agonistic anti‐CD40 and anti‐OX40 might be viewed as “adjuvant antibodies” and have been shown in diverse experimental systems to either boost immune responses or prevent the establishment of immunological tolerance. Here we describe that both these antibodies are able to prevent the induction of tolerance induced using soluble peptide antigen. However, unlike lipopolysaccharide, they are not sufficient to convert tolerance to immunity (i.e. they are not true adjuvants in this system). Using mice that are prone to either Th1 or Th2 immunity under identical immunization conditions, we show that the effects of anti‐OX40 are quantitative – boosting whichever response is dominant. In contrast, anti‐CD40 boosts Th1 immunity and converts a Th2 response to Th1. We conclude that, although these two antibodies seem to impact on the same molecular pathway of costimulation to prevent tolerance, their effects are qualitatively distinct and their use cannot be viewed as interchangeable.

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Section: Resultsmentioning

confidence: 99%

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

2006

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“…Whether other adjuvants will affect the expression of A3G needs to be examined. The overall results suggest that HSP70 might be used as an HIV-designer adjuvant in preventive and therapeutic vaccination, as HSP70 may inhibit both pre-entry transmission of HIV-1 into CD4 ϩ T cells or DC by generating CC chemokines (17,18), and postentry replication of HIV-1 by up-regulating A3G. Whereas the conventional concept of innate immunity has been that it lacks memory, this may not apply to all innate immune responses, as demonstrated recently with NK cells in delayed hypersensitivity (36).…”

Section: Discussionmentioning

confidence: 96%

“…We explored recent findings that 70-kDa heat shock protein (HSP)70 significantly inhibits HIV-1 infectivity of human CD4 ϩ T cells (K. Babaahmady, M. Singh, and T. Lehner, manuscript in preparation), and that it elicits chemokine and cytokine functions by engaging CCR5 and CD40 molecules (17)(18)(19). Indeed, we have found that in vitro stimulation of the cell surface CCR5 and CD40 molecules up-regulates A3G in CD4 ϩ T cells and DC.…”

Section: Stimulation Of Cell Surface Ccr5 and Cd40 Molecules By Theirmentioning

confidence: 99%

Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

Pido-Lopez

Whittall

Wang

et al. 2007

The Journal of Immunology

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Apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like-3G (A3G) is an intracellular innate antiviral factor that deaminates retroviral cytidine to uridine. In an attempt to harness the anti-HIV effect of A3G, we searched for an agent that would up-regulate A3G and identify the receptors involved. Stimulation of cell surface CCR5 with CCL3 and CD40 with CD40L or both molecules with microbial 70-kDa heat shock protein (HSP)70 up-regulated A3G mRNA and protein expression in human CD4+ T cells and monocyte-derived dendritic cells (DC), demonstrated by real-time PCR and Western blots, respectively. The specificity of CCR5 and CD40 stimulation was established by inhibition with TAK 779 and mAb to CD40, as well as using human embryonic kidney 293 cells transfected with CCR5 and CD40, respectively. A dose-dependent increase of A3G in CCL3- or HSP70-stimulated CD4+ T cells was associated with inhibition in HIV-1 infectivity. To differentiate between the inhibitory effect of HSP70-induced CCR5 binding and that of A3G, GFP-labeled pseudovirions were used to infect human embryonic kidney 293 cells, which showed inhibition of pseudovirion uptake, consistent with A3G being responsible for the inhibitory effect. Ligation of cell surface CCR5 receptors by CCL3 or CD40 by CD40L activated the ERK1/2 and p38 MAPK signaling pathways that induced A3G mRNA expression and production of the A3G protein. These in vitro results were corroborated by in vivo studies in rhesus macaques in which A3G was significantly up-regulated following immunization with SIVgp120 and p27 linked to HSP70. This novel preventive approach may in addition to adaptive immunity use the intracellular innate antiviral effect of A3G.

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“…Studies also suggest that a small proportion of the hsp -peptide complex is loaded onto MHC class II, leading to the stimulation of CD4 þ cells (Matsutake and Srivastava, 1999). Other receptors, such as CD36 and CD40, were identified recently on APCs that can also interact with hsp's (Panjwani et al, 2000;Wang, 2001). These receptors, once activated, cause the secretion of nonspecific inflammatory cytokines such as tumour necrosis factors and interleukins (Ishii et al, 1999).…”

mentioning

confidence: 99%

Forced expression of heat-shock protein 70 increases the secretion of Hsp70 and provides protection against tumour growth

2004

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Although heat-shock protein 70 (Hsp70) has been considered an intracellular protein, we report that Hsp70 is secreted under normal cell culture conditions by human prostate cell lines, LAPC-4, PC-3, CWR-22, RWPE-1 and -2, LNCaP, and TRAMP (transgenic adenocarcinoma mouse prostate)-C2. We found that the secretion can be enhanced by transfection with cDNA encoding for Hsp70. To verify that the Hsp70 detected in the supernatant was not secondary to cell leakage, C2 cells were cotransfected with cytoplasmic Renilla luciferase as a reporter. High levels of activities were noted in the cell extracts, while no enzyme activities were detected in the supernatants. To verify that forced oversecretion of Hsp70 could protect against tumour growth, mice were injected with C2 cells transfected with an Hsp70 DNA construct and challenged with live tumour cells. Mice injected with cells transfected with the Hsp70 DNA construct demonstrated a significantly decreased rate of tumour growth compared to those injected with empty vector. In addition, a difference in survival rate as defined by a surrogate end point was noted between the two groups. In a second experiment, we developed a cell line that stably overexpressed Hsp70. Mice injected with these cells also demonstrated a significant decrease in tumour growth and significantly increased survival.

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CD40 Is a Cellular Receptor Mediating Mycobacterial Heat Shock Protein 70 Stimulation of CC-Chemokines

Cited by 244 publications

References 51 publications

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

Forced expression of heat-shock protein 70 increases the secretion of Hsp70 and provides protection against tumour growth

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