title: 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 (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.
authors.affiliation: Mater Research, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Michael Lei
authors.initials: ML
authors.lastname: Bian
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Oscar
authors.initials: O
authors.lastname: Haigh
authors.affiliation: Mater Research, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Munster
authors.affiliation: Mater Children's Hospital, Brisbane, Queensland, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Harris
authors.affiliation: Mater Children's Hospital, Brisbane, Queensland, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cotterill
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, Wales, U.K. School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.affiliation: Mater Research, Translational Research Institute, Brisbane, Queensland, Australia QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia School of Medicine, The University of Queensland, Brisbane, Queensland, Australia slavica.vuckovic@qimrberghofer.edu.au.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male
chemical_list: D016753:Interleukin-10; D007371:Interferon-gamma