Unchecked collaboration between islet-reactive T and B lymphocytes drives type 1 diabetes (T1D). In the healthy setting, CD8 T regulatory cells (Tregs) terminate ongoing T-B interactions. We determined that specific CD8 Tregs from NOD mice lack suppressive function, representing a previously unreported regulatory cell deficit in this T1D-prone strain. NOD mice possess 11-fold fewer Ly-49 + CD8 Tregs than nonautoimmune mice, a deficiency that worsens as NOD mice age toward diabetes and leaves them unable to regulate CD4 T follicular helper cells. As IL-15 is required for Ly-49 + CD8 Treg development, we determined that NOD macrophages inadequately trans-present IL-15. Despite reduced IL-15 trans-presentation, NOD Ly-49 + CD8 Tregs can effectively transduce IL-15-mediated survival signals when they are provided. Following stimulation with an IL-15/IL-15Ra superagonist complex, Ly-49 + CD8 Tregs expanded robustly and became activated to suppress the Ag-specific Ab response. IL-15/IL-15Ra superagonist complex-activated CD8 + CD122 + T cells also delayed diabetes transfer, indicating the presence of an underactivated CD8 T cell subset with regulatory capacity against late stage T1D. We identify a new cellular contribution to anti-islet autoimmunity and demonstrate the correction of this regulatory cell deficit. Infusion of IL-15-activated CD8 Tregs may serve as an innovative cellular therapy for the treatment of T1D.

Autoimmune diseases such as type 1 diabetes (T1D) arise from unrestrained activation of effector lymphocytes that destroy target tissues. Many efforts have been made to eliminate these effector lymphocytes, but none has produced a long-term cure. An alternative to depletion therapy is to enhance endogenous immune regulation. Among these endogenous alternatives, naturally occurring Igs have been applied for inflammatory disorders but have lacked potency in antigen-specific autoimmunity. We hypothesized that naturally occurring polyclonal IgMs, which represent the majority of circulating, noninduced antibodies but are present only in low levels in therapeutic Ig preparations, possess the most potent capacity to restore immune homeostasis. Treatment of diabetes-prone NOD mice with purified IgM isolated from Swiss Webster (SW) mice (nIgM) reversed new-onset diabetes, eliminated autoreactive B lymphocytes, and enhanced regulatory T-cell (Treg) numbers both centrally and peripherally. Conversely, IgM from prediabetic NOD mice could not restore this endogenous regulation, which represents an unrecognized component of T1D pathogenesis. Of note, IgM derived from healthy human donors was similarly able to expand human CD4 Tregs in humanized mice and produced permanent diabetes protection in treated NOD mice. Overall, these studies demonstrate that a potent, endogenous regulatory mechanism, nIgM, is a promising option for reversing autoimmune T1D in humans.

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Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction.A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and also restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies. Significance StatementFine tuning of the immune response is critical to health. This fine tuning is lost in autoimmunity and cancer and must be restored to prevent undesirable outcomes. Immune cell metabolism can regulate the immune response but to date chronic interventions have been needed to produce any biologic effect. Our study in lupus-prone animals demonstrates that disease-associated changes in immune cell metabolism create a barrier to immune tolerance, which can be reset by short term metabolic treatment with 2-deoxyglucose and metformin. Metabolic therapy restored normal expression of extracellular receptors, which was required for successful immune therapy.These findings reveal the role of glycoregulation in the immune response and indicate an important interaction between immune metabolism and responsiveness to immune therapy. the spleen (Figure 1 B&C) (33). Anti-CD45RB treatment leads to a B cell dependent expansion of CD4+ Foxp3+ Tregs to promote longterm tolerance induction (23,32). We hypothesized that this B cell mobilization would expand CD4+ Foxp3+ Tregs in both SLE123 and B6 mice. Analysis of the Foxp3 + and CD25 + fractions of the CD4 + population revealed expansion of Tregs in both B6 and SLE123 mice following anti-CD45RB therapy (Figure 1 D&E). Anti-CD45RB uncovers inappropriate effector responses to tolerogenic signaling.While expansion of Tregs is important for long-term tolerance in anti-CD45RB treatment, the effector compartment must also be temporarily modulated to facilitate adequate regulation (34,35). In healthy B6 mice, anti-CD45RB inhibits the Germinal Center (GC) response and temporarily cripples antibody production (28,35). In clinical SLE and in the mouse model of disease, there is an expansion of T-follicular helper (Tfh) cells and GC B cells that collaborate to generate autoantibodies that occlude and damage the nephron...

The immune system of healthy individuals is capable of regulating autoimmunity through multiple mechanisms. In Type 1 Diabetes (T1D) we recently discovered natural IgM, although present at normal levels, is unable to perform its normal immunoregulatory function. Treating diabetic mice with IgM from healthy donors led to reversal of disease without immune depletion. To investigate the therapeutic potential of a human preparation of IgM, we administered an IgM-enriched preparation of immunoglobulin called Pentaglobin. Administration of Pentaglobin therapy reversed disease in diabetic NOD mice and boosted CD4 + Foxp3 + Tregs. Importantly, the impact of Pentaglobin on the immune system was limited to inhibiting beta cell destruction but was not immune depleting nor did it inhibit the immunization response to an irrelevant antigen. These findings indicate that inhibition of deleterious autoimmunity in T1D is possible while leaving protective immunity fully intact.