Abrogation of ICOS/ICOS ligand costimulation in NOD mice results in autoimmune deviation toward the neuromuscular system

Self Cite

Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic β cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4+ 24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4+ BDC2.5 NOD T cells in adoptive transfer experiments. CD4+ 24αβ NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αβ NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.

Section: Icos/icos-l Interaction Was Necessary For Type II Nkt Cell Rmentioning

confidence: 93%

“…The 24abNOD mice (8), BDC2.5 TCR transgenic NOD mice (BDC2.5 NOD mice) (18), and NOD.scid mice were bred at the Experimental Biomedicine Animal Facility at the University of Gothenburg. BDC2.5 NOD mice deficient for ICOS and their littermate controls (24) and Ca 2/2 BDC2.5NOD (25) were bred at Hôpital Cochin/St. Vincent de Paul (Paris, France).…”

Section: Micementioning

confidence: 99%

CD4+ Type II NKT Cells Mediate ICOS and Programmed Death-1–Dependent Regulation of Type 1 Diabetes

Kadri

Korpos

Gupta

et al. 2012

Self Cite

“…In contrast to T1D-resistant ICOS 2/2 NOD mice, ICOS blockade in BDC2.5 mice and NOD neonates or ICOS deficiency in BDC2.5 mice exacerbated T1D. However, in the reported studies, the expression or function of ICOS was solely examined on CD25-expressing (CD25 + CD69 2 T cells), not purified Foxp3 + , Tregs enriched from inflamed pancreatic sites (21)(22)(23). Notably, IL-2 therapy augments Treg numbers in the pancreas and induces the expression of various Treg-associated proteins such as Foxp3, CD25, Bcl-2, and ICOS (24).…”

mentioning

confidence: 99%

ICOS-Dependent Homeostasis and Function of Foxp3+ Regulatory T Cells in Islets of Nonobese Diabetic Mice

Kornete

Sgouroudis

Piccirillo

2012

130

145

A progressive waning in Foxp3+ regulatory T cell (Treg) functions is thought to provoke autoimmunity in the NOD model of type 1 diabetes (T1D). A deficiency in IL-2 is one of the main triggers for the defective function of Tregs in islets. Notably, abrogation of the ICOS pathway in NOD neonates or BDC2.5-NOD (BDC2.5) mice exacerbates T1D, suggesting an important role for this costimulatory pathway in tolerance to islet Ags. Thus, we hypothesize that ICOS selectively promotes Foxp3+ Treg functions in BDC2.5 mice. We show that ICOS expression discriminates effector Foxp3− T cells from Foxp3+ Tregs and specifically designates a dominant subset of intra-islet Tregs, endowed with an increased potential to expand, secrete IL-10, and mediate suppressive activity in vitro and in vivo. Consistently, Ab-mediated blockade or genetic deficiency of ICOS selectively abrogates Treg-mediated functions and T1D protection and exacerbates disease in BDC2.5 mice. Moreover, T1D progression in BDC2.5 mice is associated with a decline in ICOS expression in and expansion and suppression by intra-islet Foxp3+ Tregs. We further show that the ICOS+ Tregs, in contrast to their ICOS− counterparts, are more sensitive to IL-2, a critical signal for their survival and functional stability. Lastly, the temporal loss in ICOS+ Tregs is readily corrected by IL-2 therapy or protective Il2 gene variation. Overall, ICOS is critical for the homeostasis and functional stability of Foxp3+ Tregs in prediabetic islets and maintenance of T1D protection.

“…These results suggest that impaired generation of Tregs in the thymus of B6.Sle1.ICOS-KO mice is not the cause of their reduced frequency in the secondary lymphoid tissue. Although it was suggested that ICOS has a differentiation and regulatory function (59)(60)(61), no study has examined the role of ICOS on Tregs in lupus. Further research is necessary to understand the properties of Tregs in the context of the ICOS-sufficient and ICOS-deficient B6.Sle1 lupus-prone models.…”

Section: Cd8mentioning

confidence: 99%

Loss of Immune Tolerance Is Controlled by ICOS in Sle1 Mice

Mittereder¹,

Kuta²,

Bhat³

et al. 2016

ICOS, a member of the CD28 family, represents a key molecule that regulates adaptive responses to foreign Ags. ICOS is prominently expressed on T follicular helper (TFH) cells, a specialized CD4+ T cell subset that orchestrates B cell differentiation within the germinal centers and humoral response. However, the contribution of ICOS and TFH cells to autoantibody profiles under pathological conditions has not been thoroughly investigated. We used the Sle1 lupus-prone mouse model to examine the role of ICOS in the expansion and function of pathogenic TFH cells. Genetic deletion of ICOS impacted the expansion of TFH cells in B6.Sle1 mice and inhibited the differentiation of B lymphocytes into plasma cells. The phenotypic changes observed in B6.Sle1-ICOS–knockout mice were also associated with a significant reduction in class-switched IgG, and anti-nucleosomal IgG-secreting B cells compared with B6.Sle1 animals. The level of vascular cell adhesion protein 1, a molecule that was shown to be elevated in patients with SLE and in lupus models, was also increased in an ICOS-dependent manner in Sle1 mice and correlated with autoantibody levels. The elimination of ICOS-expressing CD4+ T cells in B6.Sle1 mice, using a glyco-engineered anti-ICOS–depleting Ab, resulted in a significant reduction in anti-nucleosomal autoantibodies. Our results indicate that ICOS regulates the ontogeny and homeostasis of B6.Sle1 TFH cells and influences the function of TFH cells during aberrant germinal center B cell responses. Therapies targeting the ICOS signaling pathway may offer new opportunities for the treatment of lupus and other autoimmune diseases.