Characterizing the circulating, gliadin-specific CD4+ memory T cells in patients with celiac disease: linkage between...

Celiac disease (CD) is a chronic, immune-mediated disorder of the gut, driven by T cells reacting locally to a distinct antigen, gliadin. Thus, CD offers the opportunity to study the T cell memory response to gliadin and whether gut tropism and T helper cell type 1 (Th1) polarization, which characterize the effector phase, are preserved in the memory progeny. It is notable that previous studies yielded conflicting results as to the presence of gliadin-specific memory CD4+ T cells in the peripheral blood of CD patients. However, we used a different and highly sensitive approach based on fluorescein-derived label dilution, whereby the memory cells are identified operationally by their greater capacity to proliferate upon re-encounter with antigen. Thus, using flow cytometry, we could resolve multiple successive generations as well as immunophenotype the dividing cells. Here, we show that the peripheral blood lymphocyte of some CD patients on a gliadin-free diet, but not healthy donors, contains a detectable population of CD4+ memory T cells specific for deamidated gliadin. Moreover, these gliadin-specific memory T cells are marked by a distinctive phenotype: They express high levels of the gut-homing beta7 integrins and primarily produce interferon-gamma and tumor necrosis factor alpha. We conclude that memory for gliadin-derived antigens within the circulating CD4+ T cells is linked with gut tropism as well as Th1 polarization.