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

Bian, Michael Lei, Haigh, Oscar, Munster, David, Harris, Mark, Cotterill, Andrew, Miles, John J., and Vuckovic, Slavica (2015) Reactivated CD4+Tm cells of T1D patients and siblings display an exaggerated effector phenotype with heightened sensitivity to activation-induced cell death. Diabetes, 64 (6). pp. 2161-2171.

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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.

Item ID: 44968
Item Type: Article (Research - C1)
ISSN: 1939-327X
Funders: Australian Postgraduate Award (APA), Mater Medical Research Institute (MMRI), National Health and Medical Research Council (NHMRC)
Date Deposited: 09 Aug 2016 04:23
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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