Epstein-Barr virus–specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential

Abstract

During acute infection, latent and lytic Epstein-Barr virus (EBV) epitope-specific CD8 ؉ T cells have a CD45RO ؉ CD45RA ؊ phenotype. However, after resolution of the infection, a large proportion of these cells, particularly those specific for lytic viral epitopes, re-express the CD45RA molecule. The role of CD8 ؉ CD45RA ؉ T cells in ongoing immunity to EBV and other viruses is unknown. We now demonstrate that, relative to their CD45RO ؉ counterparts, the EBV-specific CD8 ؉ T cells that revert to CD45RA expression after acute infectious mononucleosis are not in cell cycle, have longer telomeres, and are more resistant to apoptosis partly because of increased Bcl-2 expression. However, the EBV-specific CD8 ؉ CD45RA ؉ T cells have shorter telomeres than the total CD8 ؉ CD45RA ؉ T-cell pool and predominantly express low levels of the CCR7 chemokine receptor, indicating that they are not naive cells. In addition, EBV-specific CD8 ؉ CD45RA ؉ T cells can be induced to proliferate and exhibit potent cytotoxic activity against target cells loaded with specific pep- IntroductionThe central goal of this study was to identify the constraints that regulate the persistence of Epstein-Barr virus (EBV)-specific CD8 ϩ T cells after the resolution of acute infectious mononucleosis (AIM) to identify how the memory pool specific for this virus may be maintained. Primary encounter with EBV induces specific naive CD8 ϩ T cells to proliferate and express phenotypic markers of priming, such as CD45RO. 1,2 Most of this expanded population succumbs to apoptosis after the acute infection resolves. 3,4 The EBV-specific memory pool that escapes apoptosis consists of a mixture of cells specific for lytic and latent viral proteins, which are differentially expressed during early and late stages of the infection, respectively. 2,[5][6][7] It is unclear whether apoptosis remains a constraint on the persistence of EBV-specific CD8 ϩ T cells after the acute infection resolves and whether the cells that are specific for different viral epitopes are equally susceptible to death.A second limit to the maintenance of memory CD8 ϩ T cells after the initial infection may be telomere erosion, resulting from excessive proliferation of specific clones. 8,9 This may lead to the development of terminally differentiated end-stage effector cells that are unable to proliferate on restimulation. 10 It has been shown, however, that despite the considerable expansion of EBV-specific CD8 ϩ T cells, telomere loss does not occur during AIM because of the induction of the enzyme telomerase in these cells. 11,12 Telomere erosion does occur in the EBV-specific CD8 pool during persistent infection, 12 possibly because of frequent restimulation by virus, leading to progressively reduced telomerase induction that is insufficient to maintain telomere length in these cells. 9 The loss of some highly expanded clones of EBV-specific CD8 ϩ T cells during acute infection that are later replaced by other less expanded populations during chronic infection, 56 suggests indirectly...

EBV-Induced Human CD8+ NKT Cells Synergise CD4+ NKT Cells Suppressing EBV-Associated Tumours Upon Induction of Th1-Bias

“…For functional studies, NKT cells were purified from PBMCs or organs by flow cytometry cell sorting or the MACS bead system based on staining with the -GalCer-loaded CD1d tetramer (17,18). The -GalCerloaded CD1d tetramers were synthesised and labelled as previously described (19,20). All mAbs were purchased from R&D Systems Europe Ltd. (Abingdon, UK), except that the anti-V11 mAb and anti-V24 mAb were from CoulterImmunoTech (Marseille, France) and the anti-CD161 pAb was from Santa Cruz Biotechnology (Santa Cruz, CA).…”

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

“…The CD45RA/RO system is a classical marker combination to distinguish naive from memory T cells, with naive cells being predominantly CD45RA positive, and memory cells expressing predominantly the CD45RO isoform. However, this marker system is ambiguous, as T cell subpopulations display fluctuations in expression of CD45 isoforms and shifts from CD45RA to CD45RO upon activation and vice versa have been reported [31][32][33]. We analyzed CD45RA/RO expression on T cells during in vitro culture.…”

EFFECTS OF γс-CYTOKINES (IL-2, IL-7 AND IL-15) UPON IN VITRO MATURATION AND DIFFERENTIATION OF CD4⁺CD45RО⁺/CD8⁺CD45RО⁺ T CELLS

“…Ma A. и коллегами (2006) были получены приоритетные данные о важности IL-15 в гомеостазе CD8 + Т-клеток памяти, в отличие от наивных CD8 + лимфоцитов и CD4 + Т-клеток памяти, что, вероятно, обусловлено высокой экс-прессией β-цепи, которая имеет положительную корреляцию с чувствительностью лимфоцитов к действию IL-15 [28]. Кроме того, установлено, (13,14) Примечание. р 0 -достоверность различий по сравнению с контрольной пробой.…”

“…Т EMRA лимфоциты обладают низкой пролифе-ративной активностью, характеризуются поте-рей костимулирующих рецепторов CD28, CD27, CCR7, усиленной восприимчивостью к апоптозу, высоким цитотоксическим потенциалом, ассо-циированным с повышенным уровнем экспрес-сии FasL, перфорина и гранзима В, а также про-дукцией провоспалительных медиаторов (IFNγ и TNFα) [14,15,40]. Большинство исследователей сходятся во мнении, что Т EMRA клетки не могут быть полу-чены с помощью антигенной стимуляции, клетки с фенотипом, соответствующим Т EMRA , генериру-ются преимущественно за счет субпопуляции Т СМ при цитокиновой стимуляции [18,37].…”

“…Предполагают, что in vivo клет-ки ре-экспрессирующие молекулу CD45RA обе-спечивают устойчивую иммунную память против антигенов, которые элиминированы из организ-ма [8,12]. В соответствии с этой точкой зрения, клетки, реэкспрессирующие молекулу CD45RA, представляют собой популяцию покоящихся Т-клеток памяти, которые могут быть повторно активированы для выполнения эффекторных функций [14].…”