ABSTRACT
Type 1 diabetes (T1D) develops as a consequence of a progressive autoimmune response that destroys insulin-producing ß-cells in pancreatic islets. Because of their role(s) in controlling immune responses, considerable effort has been directed toward resolving whether regulatory T cells (Tregs) offer a clinical treatment to restore tolerance in T1D. We previously reported that in vitro-induced adaptive Treg cells (aTregs) can reverse T1D and persist as protective memory cells in the NOD mouse model. In the current study, we investigated mechanisms that regulate aTregs. We found that these FoxP3(+) aTregs expressed high levels of the IL-7 receptor, IL-7Rα, without the high affinity receptor for IL-2, CD25, which is found on natural Treg cells (nTregs). IL-7Rα expression was mirrored by the dependency of aTregs on IL-7 for persistence. IL-10 and TGF-ß, effector cytokines of aTregs, were not essential for their maintenance at the level of systemic antibody blocking. Nevertheless, IL-10 modulated cytokine production by aTregs and TGF-ß was critical for protection. aTregs were found to infiltrate islets and the expression of integrin-ß7 was required for their localization in the pancreas. Furthermore, blocking aTreg entry into the pancreas prevented their control of diabetogenic effector T cells, implying the need for local control of the autoimmune response. The distinct homeostatic regulation of aTregs independently of a response to IL-2, which is defective in T1D patients, suggests that these cells represent a translatable candidate to control the autoimmune response.
Subject(s)
Adaptive Immunity , Diabetes Mellitus, Type 1/immunology , Integrin beta Chains/immunology , Interleukin-7/immunology , Pancreas/immunology , Receptors, Interleukin-7/immunology , Signal Transduction/immunology , T-Lymphocytes, Regulatory , Adoptive Transfer , Animals , Autoimmunity , Cell Differentiation/immunology , Cell Movement/immunology , Diabetes Mellitus, Type 1/metabolism , Female , Humans , Integrin beta Chains/genetics , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-2/immunology , Interleukin-2/metabolism , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-7/deficiency , Interleukin-7/genetics , Mice , Mice, Inbred NOD , Mice, Knockout , Pancreas/metabolism , Receptors, Interleukin-7/deficiency , Receptors, Interleukin-7/genetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolismABSTRACT
Optimal immunity to microorganisms depends upon the regulated death of clonally expanded effector cells and the survival of a cohort of cells that become memory cells. After activation of naive T cells, CD44, a widely expressed receptor for extracellular matrix components, is upregulated. High expression of CD44 remains on memory cells and despite its wide usage as a "memory marker," its function is unknown. Here we report that CD44 was essential for the generation of memory T helper 1 (Th1) cells by promoting effector cell survival. This dependency was not found in Th2, Th17, or CD8(+) T cells despite similar expression of CD44 and the absence of splice variants in all subsets. CD44 limited Fas-mediated death in Th1 cells and its ligation engaged the phosphoinositide 3-kinase-Akt kinase signaling pathway that regulates cell survival. The difference in CD44-regulated apoptosis resistance in T cell subpopulations has important implications in a broad spectrum of diseases.
