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Signalling through CD30 protects against autoimmune diabetes mediated by CD8 T cells
C Kurts1, F R Carbone, M F Krummel
1The Department of Nephrology, Medizinische Hochschule, Hannover, Germany.
Abstract:
Autoantigens found on pancreatic islets can move to draining lymph nodes, where they are able to cause the activation and consequent deletion of autoreactive T cells by a mechanism termed cross-tolerance. This deletion depends on signalling through CD95 (also known as Fas), a member of the superfamily of tumour-necrosis-factor receptors. Here we describe a new mechanism that protects against autoimmunity: this mechanism involves another member of this superfamily, CD30, whose function was largely unknown. CD30-deficient islet-specific CD8-positive T cells are roughly 6,000-fold more autoaggressive than wild-type cells, with the transfer of as few as 160 CD30-deficient T cells leading to the complete destruction of pancreatic islets and the rapid onset of diabetes. We show that, in the absence of CD30 signalling, cells activated but not yet deleted by the CD95-dependent cross-tolerance mechanism gain the ability to proliferate extensively upon secondary encounter with antigen on parenchymal tissues, such as the pancreatic islets. Thus, CD30 signalling limits the proliferative potential of autoreactive CD8 effector T cells and protects the body against autoimmunity.
Insights
CD30 signaling is crucial for preventing autoimmunity by limiting the proliferation of autoreactive CD8 T cells. Without CD30, these cells become highly aggressive, leading to pancreatic islet destruction and diabetes.
Area of Science:
- Immunology
- Autoimmunity
- T cell biology
Background:
- Autoantigens on pancreatic islets trigger T cell responses in lymph nodes via cross-tolerance.
- CD95 (Fas) signaling mediates the deletion of autoreactive T cells during cross-tolerance.
Purpose of the Study:
- To investigate the role of CD30, a tumor necrosis factor receptor superfamily member, in regulating autoimmunity.
- To elucidate the mechanism by which CD30 signaling protects against autoimmune destruction of pancreatic islets.
Main Methods:
- Generation and analysis of CD30-deficient islet-specific CD8-positive T cells.
- Assessment of T cell autoaggressiveness and proliferative capacity in vivo.
- Evaluation of pancreatic islet destruction and onset of diabetes.
Main Results:
- CD30-deficient CD8 T cells were approximately 6,000-fold more autoaggressive than wild-type cells.
- Transfer of as few as 160 CD30-deficient T cells caused complete islet destruction and rapid diabetes onset.
- Absence of CD30 signaling allowed activated T cells, not deleted by CD95, to proliferate extensively upon antigen re-encounter.
Conclusions:
- CD30 signaling is essential for limiting the proliferative potential of autoreactive CD8 effector T cells.
- CD30 plays a critical role in preventing autoimmunity by suppressing the development of aggressive T cell responses against self-antigens in pancreatic islets.
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