Manipulation of CD98 Resolves Type 1 Diabetes in Nonobese Diabetic Mice

Abstract

The interplay of CD4+ and CD8+ T cells targeting autoantigens is responsible for the progression of a number of autoimmune diseases, including type 1 diabetes mellitus (T1D). Understanding the molecular mechanisms that regulate T cell activation is crucial for designing effective therapies for autoimmune diseases. We probed a panel of Abs with T cell-modulating activity and identified a mAb specific for the H chain of CD98 (CD98hc) that was able to suppress T cell proliferation. The anti-CD98hc mAb also inhibited Ag-specific proliferation and the acquisition of effector function by CD4+ and CD8+ T cells in vitro and in vivo. Injection of the anti-CD98hc mAb completely prevented the onset of cyclophosphamide-induced diabetes in NOD mice. Treatment of diabetic NOD mice with anti-CD98hc reversed the diabetic state to normal levels, coincident with decreased proliferation of CD4+ T cells. Furthermore, treatment of diabetic NOD mice with CD98hc small interfering RNA resolved T1D. These data indicate that strategies targeting CD98hc might have clinical application for treating T1D and other T cell-mediated autoimmune diseases.

Nutrient transporters: the Achilles’ heel of anabolism

“…While the effect of 4F2hc loss on amino acid uptake in this disease model was not considered, it was also not excluded. Similar to results with the conditional T cell knockout mouse, an antibody to 4F2hc surface domains blocked the development of type 1 diabetes in a mouse model; however, as T cells require 4F2hc for both the nutrient influx that supports proliferative metabolism and for integrin-mediated cell-cell contact and migration, the loss of both of these activities may contribute to the protection from experimental diabetes [43, 45]. In sum, as 4F2hc has a dual role in regulating amino acid transporter and β integrin activity, it is important to consider both effects when interpreting experimental results.…”

Interleukin-18 up-regulates amino acid transporters and facilitates amino acid–induced mTORC1 activation in natural killer cells

“…For example, the roles of CD98/LAT1 in T cells have been extensively studied in the context of infection and autoimmune models. Anti-CD98 mAb completely prevented the onset of cyclophosphamide-induced diabetes in NOD mice, coincident with decreased proliferation of pathogenic CD4 ϩ T cells (51). T cell-specific deletion of LAT1 resulted in dramatically reduced T cell clonal expansion in an autoimmune model (52).…”

CD98 Heavy Chain Is a Potent Positive Regulator of CD4+ T Cell Proliferation and Interferon-γ Production In Vivo

“…Our group has previously demonstrated that an anti-CD98hc blocking antibody had a therapeutic effect on spontaneously developed type 1 diabetes in NOD mice [ 13 ]. Another group also showed that T cell-specific CD98hc deficiency prevented the development of type1 diabetes and experimental autoimmune encephalomyelitis [ 12 ].…”

“…Fluorochrome-conjugated anti-CD3, CD4, CD8, CD44, CD25, and CD62L mAbs were purchased from BioLegend (CA, USA). Anti-CD98hc antibody was described previously [ 13 ]. APC-conjugated AnnexinV was purchased from BD Biosciences (NJ, USA).…”

“…It has been shown that CD98hc controls T cell activation [ 11 ] and a recent report in which mice had Slc3a2 deleted only in their T cells showed that CD98hc was important for T cell proliferation, but was not essential for T cell effector functions [ 12 ]. We previously reported that an anti-CD98hc mAb that could inhibit T cell proliferation suppressed the development of type1 diabetes [ 13 ]. These results suggest that CD98hc is crucial for T cell-mediated adaptive immune responses.…”