Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses

Shi, Yan; Zheng, Wanyong; Rock, Kenneth L.

doi:10.1073/pnas.260497597

Cited by 206 publications

(186 citation statements)

References 32 publications

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“…In support of this notion, cytosol obtained from healthy cells has adjuvant activity, indicating that DAMPs are present intracellularly 11 . It isn't yet clear whether there are also membraneassociated DAMPs, but nuclei have little adjuvant activity 11 . In living cells, these intracellular molecules are normally sequestered from the innate immune system by the plasma membrane.…”

Section: The Danger Hypothesismentioning

confidence: 71%

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How dying cells alert the immune system to danger

2008

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When a cell dies in vivo the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes, that is, it is part of normal physiological processes, then there is little threat to the organism. In this situation, little else is done other than removing the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized. The importance of this process to host defence and disease pathogenesis has only been appreciated relatively recently. This article will review our current knowledge of these processes.The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection upon repeat exposure to a pathogen. Through subsequent studies by Von Behring and others it rapidly became apparent that the immune system had the potential to respond not only to whole microorganisms, but to virtually any molecule that was "foreign" to the host. However, whereas injection of such molecules would often provoke a robust immune response, this did not invariably occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants [G]) that could boost immune responses to co-administered antigens. Adjuvants were typically of microbial origin and became widely used to promote the effectiveness of immunizations. In the 1960s, Dresser showed that a foreign protein when highly purified would only elicit an immune response if it was admixed with a microbial adjuvant 1 . Injected by itself, the antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used because they were part of standard operating procedures.In 1989 Janeway put these empirical observations into a conceptual framework 3 (Fig. 1). He proposed that the immune system did not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea here was that the immune system evolved to protect organisms against microorganisms and this discrimination between infectious versus noninfectious antigens focused defences on real threats rather than innocuous situations.At this time, it was already recognized that in order to stimulate T cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen presenting cell (APC). Moreover, it was further known that APCs also provided additional costimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (Fig. 1). He postulated that the discrimination between infectious and noninfectious non-self molecules was made by the APCs of the innate immune system through receptors that would recognize pathogen-associated molecular patterns (PAMP...

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Section: The Danger Hypothesismentioning

confidence: 71%

“…When healthy cells were treated with protein synthesis inhibitors, their endogenous adjuvant activity was not reduced 11 . Moreover, when healthy cells were killed instantaneously by freeze-thawing, they provided adjuvant activity 10 11.…”

Section: The Danger Hypothesismentioning

confidence: 98%

How dying cells alert the immune system to danger

2008

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“…Given the large body of evidence supporting the adjuvant effect of tissue damage (11,15,(17)(18)(19)(20)(21), it is surprising that CTL-mediated tissue destruction has such a minimal immunological impact. Moreover, the CTLs themselves should produce inflammatory cytokines, which might be expected to promote immunity.…”

Section: Ifn-␥ Productionmentioning

confidence: 99%

“…While CTLmediated tissue destruction will release self-antigens through target cell apoptosis, this cell death may be accompanied by the production of CTL derived inflammatory cytokines such as TNF␣ and IFN-␥ (16) or with the release of inflammatory components of the degraded extracellular matrix such as heparan sulfate and hyaluronan oligosaccharides (17,18). Depending on the extent of tissue destruction, secondary necrosis may also accompany CTL damage, leading to the release of intracellular components of potential immunogenicity (19)(20)(21). Collectively, these signals may be sufficient to overcome the immunosuppressive nature of apoptotic material and drive T cell priming against any released antigens.…”

mentioning

confidence: 99%

Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Parish

Waithman

Davey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Autoimmune diseases tend to be chronic and progressive, but how these responses are sustained is not clear. One cell type that might contribute to autoimmunity is the cytotoxic T lymphocyte (CTL), which, as a consequence of causing tissue destruction and production of cytokines, could provide a sustained supply of antigen and inflammatory signals for dendritic cells to maintain immune stimulation. Here we examined whether such CTL-mediated tissue damage alone could provide antigen in the right context to recruit immune effectors and sustain autoimmunity. We show that while CTL-mediated tissue damage caused the release of self-antigens that stimulated the proliferation of naive autoreactive CD8 ؉ T cells, such responses failed to precipitate disease and, instead, led to deletional tolerance. These findings indicate that despite the capacity of CTLs to produce inflammatory cytokines and to cause tissue damage, their responses are not sustaining, but instead favor induction of self-tolerance.antigen presentation ͉ apoptosis ͉ autoimmunity ͉ CTL ͉ T cell

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“…This leads to the spillage of cellular contents in the extra-cellular milieu which might provoke inflammatory reactions in neighbouring cells (Matzinger, 1994;Shi et al, 2000). Here, presence of GbpA was found to increase cell membrane permeability in host cells which is indicative of cell necrosis.…”

Section: Discussionmentioning

confidence: 91%