Reactivated CD4+Tm cells of T1D patients and siblings display an exaggerated effector phenotype with heightened sensitivity to activation-induced cell death

Abstract

Dysfunction in effector memory has been proposed to contribute to autoimmunity in type 1 diabetes (T1D). Using a unique cohort of age- And sex-matched T1D patients, nonaffected siblings, and unrelated control children, we undertook a detailed analysis of proliferation, activation, effector responses, and apoptosis in reactivated CD4+Tm cells during T-cell receptor stimulation. Across cohorts, there was no difference in the proliferation of reactivated CD4+Tm cells. In T1D patients and siblings, CD4+Tm cells easily acquired the activated CD25+ phenotype and effectively transitioned from a central (CD62L+Tcm) to an effector memory (CD62L2Tem) phenotype with an elevated cytokine "signature" comprising interferon (IFN)-g and interleukin-10 in T1D patients and IFN-g in siblings. This amplified Tem phenotype also exhibited an exaggerated immune shutdown with heightened sensitivity to activation-induced cell death and Fas-independent apoptosis. Apoptosis resulted in the elimination of one-half of the effector memory in T1D patients and siblings compared with one- Third of the effector memory in control subjects. These data suggest genetic/environment-driven immune alteration in T1D patients and siblings that manifests in an exaggerated CD4+Tem response and shutdown by apoptosis. Further immunological studies are required to understand how this exaggerated CD4+Tem response fits within the pathomechanisms of T1D and how the effector memory can be modulated for disease treatment and/or prevention.