Cutting Edge: Elimination of an Endogenous Adjuvant Reduces the Activation of CD8 T Lymphocytes to Transplanted Cells and in an Autoimmune Diabetes Model

Shi, Yan; Galusha, Shelly A.; Rock, Kenneth L.

doi:10.4049/jimmunol.176.7.3905

Cited by 74 publications

(62 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We reported that cell death releases endogenous adjuvants, such as uric acid, that strongly activate DCs (31,32). However, if such a factor is removed, autoreactive T cells show substantially reduced response to an islet-specific transgenic neo Ag (OVA, in RIP-OVA diabetes model) (33). Removal of pancreatic LNs leads to decreased diabetes incidence, suggesting that DC migration to secondary lymphoid organs is critical (34).…”

Section: Discussionmentioning

confidence: 99%

High Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

Oskouie

Shameli

Yang

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Adenosine has been established as an important regulator of immune activation. It signals through P1 adenosine receptors to suppress activation of T cells and professional APCs. Adenosine deaminase (ADA) counters this effect by catabolizing adenosine. This regulatory mechanism has not been tested in a disease model in vivo. Questions also remain as to which cell types are most sensitive to this regulation and whether its dysregulation contributes to any autoimmune conditions. We approached this issue using the NOD model. We report that ADA is upregulated in NOD dendritic cells, which results in their exuberant and spontaneous activation. This, in turn, triggers autoimmune T cell activation. NOD DCs deficient in ADA expression have a greatly reduced capacity to trigger type I diabetes. We also provide evidence that although many cell types, particularly T cells, have been implicated as the suppression targets by adenosine in an in vitro setting, DCs also seem to be affected by this regulatory mechanism. Therefore, this report illustrates a role of ADA in autoimmunity and suggests a potential target for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

High Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

Oskouie

Shameli

Yang

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Monosodium urate crystals were shown to stimulate DCs in vitro and have adjuvant activity in vivo. Importantly, the adjuvant activity of cells was reduced by enzymatic depletion of uric acid, indicating that it is a major DAMP, at least in some cells 27 20. However, uric-acid depletion did not eliminate all endogenous adjuvant activity from dead cells and cytosol was found to contain other activity 27 20, indicating that there must be other important DAMPs.…”

Section: Uric Acidmentioning

confidence: 99%

“…to the exposure of cellular antigens). However, there is limited evidence that the depletion of one DAMP (uric acid, discussed below) can reduce the activation of T cells to an autoantigen 20 , some cancers 21 and a transplanted cell line 20 . However, the loss of this DAMP did completely inhibit these responses and for responses to some other transplanted tumours or tissues the loss had no effect (A. Hearn, Y. Shi, D. Greiner and KLR, unpublished).…”

Section: Danger and Diseasementioning

confidence: 99%

How dying cells alert the immune system to danger

2008

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…Various antigen dependent and antigen independent mechanisms are responsible for the nephropathy associated with uric acid. Studies have found the role of uric acid in activation of dendritic cells to host antigens, activation of CD8 T cells to transplanted cells and activation of T cell response to dendritic cell based vaccines 9,10 . Uric acid is also implicated in activation of B cells and IL-2 receptor on monocyte via MyD88 dependent signaling pathway [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%