Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

Few therapeutic and diagnostic tools specifically aim at T cells in autoimmune disorders, but are T cells a narrow target in these diseases? Lessons may be learned from celiac disease (CeD), one of the few autoimmune disorders where the T cell driving antigens are known, i.e. dietary gluten proteins. T cell clonotypes specific to gluten are expanded, persist for decades and express a distinct phenotype in CeD patients. Cells with this phenotype are increased also in other autoimmune conditions. Accordingly, disease-specific CD4+ T cells form an immunological scar in CeD and probably other autoimmune disorders. We discuss approaches how such T cells may be targeted for better treatment and diagnosis via their antigen specificity or via their expression of characteristic phenotypic markers. CD4+ T cells specific for gluten antigen in patients with celiac disease have a narrow phenotype and they persist for decades.Gluten-specific CD4+ T cells appear to drive the development of celiac disease, and CD4+ T cells with overlapping phenotypical and functional properties may drive the pathogenic immune responses of other autoimmune diseases.Antigen-specific T cells could be efficient targets for therapy. Several approaches are conceivable. Disease-driving CD4+ T cells can be silenced by mechanisms of immune deviation or elimination, by reactivation induced cell death or by use of antibodies targeting characteristic phenotypic markers, including activation markers. Further, disease-driving CD4+ T cells can be controlled by agonists of checkpoint inhibition or antagonists of checkpoint stimulation as well as by interfering with homing to specific or inflamed tissue.