Spi6 Protects Alloreactive CD4+ But Not CD8+ Memory T Cell From Granzyme B Attack by Double‐Negative T Regulatory Cell. Issue 3 (12th February 2014)

• Record Type: Journal Article
• Authors: Su, Y.; Jevnikar, A. M.; Huang, X.; Lian, D.; Zhang, Z.‐X.
• Is Part Of: American journal of transplantation. Volume 14:Issue 3(2014:Mar.)
• Page Start: 580
• Page End: 593
• Publication Date: 2014-02-12
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.12614
• Languages: English
• ISSNs: 1600-6135

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajt12614-sec-0001" sec-type="section"> <p>Memory T (Tm) cells pose a major barrier to long‐term transplant survival. Whether regulatory T cells (Tregs) can control them remains poorly defined. Previously, we established that double‐negative (DN) Tregs suppress effector T (Teff) cells. Here, we demonstrate that DN Tregs effectively suppress CD4<sup>+</sup>/CD8<sup>+</sup> Teff and CD8<sup>+</sup> Tm but not CD4<sup>+</sup> Tm cells, whereas the suppression on CD8<sup>+</sup> Tm is abrogated by perforin (PFN) deficiency in DN Tregs. Consistently, in a BALB/c to B6‐Rag1<sup>−/−</sup> skin transplantation, transfer of DN Tregs suppressed the rejection mediated by CD4<sup>+</sup>/CD8<sup>+</sup> Teff and CD8<sup>+</sup> Tm cells (76.0 ± 4.9, 87.5 ± 5.0 and 63.0 ± 4.7 days, respectively) but not CD4<sup>+</sup> Tm cells (25.3 ± 1.4 days). Both CD8<sup>+</sup> effector memory T and central memory T compartments significantly reduced after DN Treg transfer. CD4<sup>+</sup> Tm highly expresses granzyme B (GzmB) inhibitor serine protease inhibitor‐6 (Spi6). Spi6 deficiency renders CD4<sup>+</sup> Tm susceptible to DN Treg suppression. In addition, transfer of WT DN Tregs, but not PFN<sup>−/−</sup> DN Tregs, inhibited the skin allograft rejection mediated by Spi6<sup>−/−</sup> CD4<sup>+</sup> Tm (75.5 ± 7.9 days). In conclusion, CD4<sup>+</sup> and CD8<sup>+</sup> Tm cells differentially respond to DN Tregs' suppression. The GzmB resistance conferred by Spi6 in CD4<sup>+</sup> Tm cells might hint at the physiological significance of Tm persistence.</p> </sec> </abstract>