Rethinking Type 1 Diabetes as More Than a T Cell Disease

Type 1 diabetes (T1D) has traditionally been viewed as a predominantly T cell-mediated disease, a framework reflected in the development of T cell-directed therapies such as the anti-CD3 antibody teplizumab. Although anti-CD3 therapy can alter disease progression, responses are variable, highlighting the need to better understand the broader immune networks contributing to T1D. Growing evidence points to an important role for B cells, which can present antigen, secrete cytokines, produce autoantibodies, and promote self-reactive T cell responses. B cell depletion has also been shown to transiently preserve C-peptide in newly diagnosed patients before the effect wanes. The population at the center of this study is a distinct CD226⁺ B cell subset with pro-inflammatory characteristics, and the question is what drives it.

Establishing whether a specific B cell subset contributes to disease requires more than an observed association in patient blood. It requires identifying the population, tracing the signals that regulate it, and then testing whether interrupting those signals changes disease course in a controlled in vivo system.

What Drives CD226⁺ B Cells: The Monocyte–IL-15 Axis

A study from the Zhao and Zhou laboratories at the Second Xiangya Hospital of Central South University set out to characterize CD226⁺ B cells in T1D and identify what regulates them. CD226 is an activating co-stimulatory receptor, and polymorphisms in the CD226 gene have been associated with susceptibility to several autoimmune diseases, including T1D.

Across cohorts of T1D, latent autoimmune diabetes in adults (LADA), type 2 diabetes, and healthy control participants, the proportion of CD226⁺ B cells was elevated in T1D and LADA and correlated with clinical measures of disease severity. CD226⁺ B cells were not similarly elevated in type 2 diabetes despite hyperglycemia, supporting an association with autoimmune rather than hyperglycemic conditions.

Functionally, CD226⁺ B cells from patients and NOD mice showed heightened activation and pro-inflammatory characteristics, with increased proliferation in NOD mice and a glycolytic metabolic phenotype demonstrated in patient-derived cells. Transcriptomic and inhibitor data also implicated NF-κB signaling in this phenotype.

The study identified interleukin-15 (IL-15) produced by monocytes and macrophages as an upstream signal. IL-15 signaling through IL-15Rβ and the common γ chain CD132 on B cells promoted CD226 expression and pro-inflammatory activity, linking an innate immune signal to an adaptive immune-cell population.

How the In Vivo Argument Was Built

Mapping a pathway in patient samples establishes an association; testing whether the pathway contributes to disease requires perturbing it in a controlled model. The in vivo work in NOD mice, including a cyclophosphamide-accelerated model, used antibody-based interventions to test the pathway at several points.

Prophylactic blockade of CD132 tested whether common γ-chain signaling, including IL-15 signaling, contributed to disease onset. Anti-CD132 (clone 3E12), administered against its matched anti-IgG2b isotype control, protected NOD mice from cyclophosphamide-accelerated diabetes, reducing hyperglycemia and insulitis while lowering the proportion of CD226⁺ B cells. Because CD132 is shared by several cytokine receptors, this result implicated the broader signaling pathway but could not by itself isolate the contribution of IL-15.

Neutralizing IL-15 directly provided an orthogonal test of the pathway. Anti-IL-15 (clone AIO.3), run against its anti-IgG2a isotype control, produced protective effects comparable to CD132 blockade, strengthening the evidence that IL-15 contributes to the observed phenotype rather than attributing the effect solely to broader common γ-chain signaling¹.

Testing therapeutic potential after disease onset required asking whether CD132 blockade could improve the response to a T cell-directed therapy. Anti-CD3 F(ab′)₂ (clone 145-2C11), administered with an IgG F(ab′)₂ isotype control, served as the anti-CD3 treatment in diabetic NOD mice. Combined with anti-CD132, it increased remission rates and reduced blood glucose and insulitis compared with anti-CD3 alone. The combination also reduced CD226⁺ B cell frequency and activation and reduced T cell activation, as measured by CD69 expression on CD4⁺ and CD8⁺ T cells¹.

Featured Products

Bio X Cell Relevance

This study used antibody-based interventions at several points in the proposed pathway, including CD132 blockade, direct IL-15 neutralization, and anti-CD3 F(ab′)₂ treatment. The anti-CD132 and anti-IL-15 experiments provided complementary approaches to testing IL-15 signaling, while the combination experiment evaluated CD132 blockade alongside a T cell-directed treatment in diabetic NOD mice.

Bio X Cell's in vivo portfolio includes antibodies for depletion, neutralization, and blockade, as well as F(ab′)₂ fragments, Fc-engineered variants, recombinant antibodies, and multispecific formats for studies requiring different experimental approaches.

References

1. Li J, Liang X, Zhao M, et al. Monocyte/macrophage-derived interleukin-15 mediates the pro-inflammatory phenotype of CD226+ B cells in type 1 diabetes. eBioMedicine. 2025;120:105946. https://doi.org/10.1016/j.ebiom.2025.105946