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 (CD62L−Tem) phenotype with an elevated cytokine “signature” comprising interferon (IFN)-γ and interleukin-10 in T1D patients and IFN-γ 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.

Type 1 diabetes is a T cell mediated autoimmune disease, often presented in children.Development of T1D is a chronic progression, wherein memory CD4 + T cells (CD4 + Tm)are believed to play a pivotal role in mediating autoimmune responses. It has been proposed that dysfunction in effector memory cells may contribute to autoimmunity in T1D.Using a unique cohort of age-and gender-matched children with T1D, their non-diabetic siblings and unrelated healthy control children, we undertook a detailed immunological study, including circulating CD4 + Tm cell counts, and activation, proliferation, effector responses and apoptosis in reactivated CD4 + Tm cells during TCR stimulation induced by anti-CD3/anti-CD28 mAb.We found T1D was associated with a reduced circulating CD4 + Tm cell count, and a similar reduction in circulating CD4 + Tm cells was also evident in the siblings. In both children with 3 CD8+ T cell lineages) as well as in response to islet-specific antigen challenge is warranted in further studies. Nonetheless, this study provides new insights for further defining mechanisms underlying T1D pathophysiology, and illuminates specific immune cell lineages, biologically relevant surface receptors, cytokines, and biochemical pathways for therapeutic targeting.4