Celiac disease plasma cells recognize the active form of transglutaminase 2 with and without bound substrate

Autoantibodies to the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease, and TG2-specifc plasma cells are abundant in the celiac gut lesion. The production of antibodies by effector B cells (i.e. plasma cells) are believed to result from collaboration between TG2-specific B cells and gluten-specific CD4⁺ T cells - a collaboration facilitated by formation of TG2-gluten enzyme-substrate complexes. Since binding of substrate is associated with conformational changes in TG2, we sought to address whether the conformation of TG2 influences plasma cell reactivity. Using effector molecules to lock TG2 in distinct conformational states, we here demonstrate that a fraction of TG2-specific plasma cells and patient-derived monoclonal antibodies (mAbs) do not recognize the GDP-bound inactive enzyme, while they bind equally well to effector-free and substrate-bound TG2. TG2-specific mAbs generated from naive B cells were generally more sensitive to conformational changes than mAbs generated from plasma cells. Our results support a model where B cells recognizing certain TG2 epitopes undergo preferential plasma cell differentiation based on their ability to bind catalytically active TG2 that can cycle through substrate-bound and unbound states.