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: 2161-2171. doi:10.2337/db14-1151

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Author Bian, Michael Lei
Haigh, Oscar
Munster, David
Harris, Mark
Cotterill, Andrew
Miles, John J.
Vuckovic, Slavica
Title Reactivated CD4+Tm cells of T1D patients and siblings display an exaggerated effector phenotype with heightened sensitivity to activation-induced cell death
Formatted title
Reactivated CD4+Tm cells of T1D patients and siblings display an exaggerated effector phenotype with heightened sensitivity to activation-induced cell death
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
1939-327X
Publication date 2015-06-01
Sub-type Article (original research)
DOI 10.2337/db14-1151
Open Access Status Not Open Access
Volume 64
Issue 6
Start page 2161
End page 2171
Total pages 11
Place of publication Alexandria, VA, United States
Publisher American Diabetes Association
Collection year 2016
Language eng
Formatted 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 (CD62LTem) 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.
Keyword Fas
Apoptosis
Autoimmunity
Mice
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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