Polyclonal Adaptive Regulatory CD4 Cells That Can Reverse Type I Diabetes Become Oligoclonal Long-Term Protective Memory Cells

Abstract

Type 1 diabetes is a CD4 cell-dependent disease that results from destruction of insulin-producing β cells in pancreatic islets. An ideal therapy would reverse diabetes shortly after onset when islet function in not yet fully ablated, and also prevent re-emergence of disease through the generation of memory cells that control the autoimmune response. In this study, we show that adaptive/induced polyclonal regulatory (TR) cells, which contain islet-reactive cells, fulfill these criteria in the NOD mouse model. CD4 cells induced to express FoxP3, IL-10, and TGF-β1 in response to TCR signaling and TGF-β1 can reverse diabetes with clinical restoration of prediabetic serum levels of IL-10. Unlike naturally occurring TR cells, these adaptive TR cells persist indefinitely (>1 year) as FoxP3+, CD25− memory cells that self-renew. Establishment of memory is accompanied by narrowing of the T cell repertoire to usage of a single TCR β-chain, Vβ11, implying selection by Ag. With islet-specific adaptive TR cells, we show that memory is functionally stable and transferable. Therefore, adaptive TR cells, which can be readily generated from normal CD4 populations and become focused by Ag with induction of memory, may provide a treatment and a vaccine for the long-term cure of diabetes making them attractive as immunotherapeutic agents.

Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity

“…Studies have shown that both thymic-derived nTregs and in vitroexpanded iTregs can be used to prevent disease in mouse models of human disease when given prior to or very shortly after disease induction (14)(15)(16)18). The use of Ag-specific as opposed to polyclonal Tregs is more attractive as a cellular therapy because of the potential to target immunosuppression to the affected organ while leaving the rest of the immune system capable of mounting normal responses against infection or cancer.…”

“…iTregs share functional capabilities with nTregs in that they are suppressive both in vitro and in vivo (9)(10)(11)(12)(13). For example, the transfer of iTregs reduced the severity of experimental autoimmune encephalmyelitis, prevented the development of diabetes and autoimmune gastritis (AIG), and alleviated the severity of viral-induced ocular inflammatory disease (12)(13)(14)(15)(16)(17)(18)(19).…”

Abortive activation of CD4 T cell responses during competitive priming in vivo

“…One possibility is that persistence of a peptide on the class II molecule provides an advantage for stable CD4 memory generation and maintenance. Although it is known that antigen persistence is not required to generate memory cells (42)(43)(44)(45), it is possible that continued opportunities to engage the CD4 T cells agonist ligand provides some advantage in the quantity or quality of memory T cells (29,(46)(47)(48)(49). Also, engagement of CD4 T cells, particularly follicular helper T cells, with antigen-specific B cells in the germinal center may be most efficient and long-lived for stable peptide:class II complexes (23).…”

Tolerance and Autoimmunity in Type 1 Diabetes

“…The idea is to compensate a presumed deficiency in tolerogenic cells or tolerogenic cell/molecular signaling pathways by transferring cell types with immunomodulatory capacity. Specifically, both ex vivo expanded Tregs or induced CD4 + CD25 + Foxp3 + Tregs (iTreg) have been shown to control ongoing autoimmunity and either prevent progression to diabetes or protect syngeneic islet grafts and/or allow -cell recovery, thus inducing diabetes remission in NOD mice (Tang & Bluestone, 2006;Weber et al, 2006;Luo et al, 2007;Godebu et al, 2008). It is unclear whether antigen specificity is critically important in this approach because both nonspecifically-expanded polyclonal or induced Tregs and islet antigen-specific Tregs have shown efficacy in controlling the disease.…”