B cell depletion in autoimmune diabetes: insights from murine models.

INTRODUCTION: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear. AREAS COVERED: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells. EXPERT OPINION: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations.

B1 cells promote pancreas infiltration by autoreactive T cells.

The entry of autoreactive T cells into the pancreas is a critical checkpoint in the development of autoimmune diabetes. In this study, we identify a role for B1 cells in this process using the DO11 x RIP-mOVA mouse model. In transgenic mice with islet-specific T cells, but no B cells, T cells are primed in the pancreatic lymph node but fail to enter the pancreas. Reconstitution of the B1 cell population by adoptive transfer permits extensive T cell pancreas infiltration. Reconstituted B1 cells traffic to the pancreas and modify expression of adhesion molecules on pancreatic vasculature, notably VCAM-1. Despite substantial pancreas infiltration, islet destruction is minimal unless regulatory T cells are depleted. These data identify a role for B1 cells in permitting circulating islet-specific T cells to access their Ag-bearing tissue and emphasize the existence of multiple checkpoints to regulate autoimmune disease.

Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity.

The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.

Release from regulatory T cell-mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21.

The activity of regulatory T cells (Treg) is widely accepted to play a central role in preventing pathogenic immune responses against self-Ags. However, it is not clear why such regulation breaks down during the onset of autoimmunity. We have studied self-Ag-specific Treg during the induction of spontaneous diabetes. Our data reveal a shift in the balance between regulatory and pathogenic islet-reactive T cells in the pancreas-draining lymph nodes during disease onset. Treg function was not compromised during disease initiation, but instead conventional T cells showed reduced susceptibility to Treg-mediated suppression. Release from Treg suppression was associated with elevated levels of IL-21 in vivo, and provision of this cytokine abrogated Treg suppression in vitro and in vivo. These data suggest that immunological protection of a peripheral tissue by Treg can be subverted by IL-21, suggesting new strategies for intervention in autoimmunity.