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JCI Insight. 2019 Feb 21;4(4). pii: 126136. doi: 10.1172/jci.insight.126136. eCollection 2019 Feb 21.

B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes.

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Systems Immunology Program.
Diabetes Program, and.
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.


Costimulatory interactions control T cell activation at sites of activated antigen-presenting cells, including B cells. Blockade of the CD28/CD80/CD86 costimulatory axis with CTLA4Ig (abatacept) is widely used to treat certain autoimmune diseases. While transiently effective in subjects with new-onset type 1 diabetes (T1D), abatacept did not induce long-lasting immune tolerance. To elucidate mechanisms limiting immune tolerance in T1D, we performed unbiased analysis of whole blood transcriptomes and targeted measurements of cell subset levels in subjects from a clinical trial of abatacept in new-onset T1D. We showed that individual subjects displayed age-related immune phenotypes ("immunotypes") at baseline, characterized by elevated levels of B cells or neutrophils, that accompanied rapid or slow progression, respectively, in both abatacept- and placebo-treated groups. A more pronounced immunotype was exhibited by a subset of subjects showing poor response (resistance) to abatacept. This resistance immunotype was characterized by a transient increase in activated B cells (one of the cell types that binds abatacept), reprogrammed costimulatory ligand gene expression, and reduced inhibition of anti-insulin antibodies. Our findings identify immunotypes in T1D subjects that are linked to the rate of disease progression, both in placebo- and abatacept-treated subjects. Furthermore, our results suggest therapeutic approaches to restore immune tolerance in T1D.


Autoimmunity; B cells; Neutrophils; T cells; Therapeutics

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