The CD27− subset of peripheral blood memory CD4+ lymphocytes contains functionally differentiated T lymphocytes that develop by persistent antigenic stimulation in vivo

Jong, R. De; Brouwer, Margreet; Hooibrink, Berend; Pouw-Kraan, Tineke van der; Miedema, Frank; Lier, R. A. van

doi:10.1002/eji.1830220418

Cited by 140 publications

(105 citation statements)

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“…CD27 + and CD27‐ DN class‐switched memory cells share overlapping clones23, and the transition of B cells between these memory pools may be due to downregulation of CD27 secondary to chronic antigen stimulation 24. Recent work in rheumatoid arthritis indicates that the expansion of relatively short‐lived DN B cells reflects a state of chronic B‐cell hyperactivity that is responsive to IL‐6R inhibition 25.…”

Section: Discussionmentioning

confidence: 99%

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Kowarik

Astling

Gasperi

et al. 2017

Ann Clin Transl Neurol

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ObjectivesNeuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system (CNS) targeted against aquaporin‐4 (AQP4). The origin and trafficking of AQP4‐specific B cells in NMOSD remains unknown.MethodsPeripheral (n = 7) and splenic B cells (n = 1) recovered from seven NMOSD patients were sorted into plasmablasts, naïve, memory, and CD27‐IgD‐ double negative (DN) B cells, and variable heavy chain (VH) transcriptome sequences were generated by deep sequencing. Peripheral blood (PB) VH repertoires were compared to the same patient's single‐cell cerebrospinal fluid (CSF) plasmablast (PB) VH transcriptome, CSF immunoglobulin (Ig) proteome, and serum Ig proteome. Recombinant antibodies were generated from paired CSF heavy‐ and light chains and tested for AQP4 reactivity.ResultsApproximately 9% of the CSF VH sequences aligned with PB memory B cells, DN B cells, and plasmablast VH sequences. AQP4‐specific VH sequences were observed in each peripheral B‐cell compartment. Lineage analysis of clonally related VH sequences indicates that CSF AQP4‐specific B cells are closely related to an expanded population of DN B cells that may undergo antigen‐specific B‐cell maturation within the CNS. CSF and serum Ig proteomes overlapped with the VH sequences from each B‐cell compartment; the majority of matches occurring between the PB VH sequences and serum Ig proteome.InterpretationDuring an acute NMOSD relapse, a dynamic exchange of B cells occurs between the periphery and CNS with AQP4‐specific CSF B cells emerging from postgerminal center memory B cells and plasmablasts. Expansion of the PB DN B‐cell compartment may be a potential biomarker of NMOSD activity.

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Section: Discussionmentioning

confidence: 99%

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Kowarik

Astling

Gasperi

et al. 2017

Ann Clin Transl Neurol

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“…In EM (CD45RA À CCR7 À ) Th cells [30], Hopx expression was up-regulated 18-fold, as compared with naïve Th cells. In ''terminally differentiated'' EM (CD45RA À CCR7 À CD27 À ) Th cells [31,32], Hopx was up-regulated 38-fold, and 45-fold in EM (CD45RA À CCR7 À CCR5 1 ) Th1 cells [33], again in comparison to naïve Th cells. In regulatory (CD25 hi CD127 À ) Th cells [34] and in Th2 EM (CD45RA À CCR7 À CRTh2 1 ) (CRTh2, chemoattractant receptor-homologous molecule expressed on Th2 cells) cells [35] (Fig.…”

Section: Hopx Expression Is Induced By T-betmentioning

confidence: 95%

“…In Th cells isolated ex vivo, expression of Hopx is restricted to presumptive Th1 effector/ memory cells, as is evident from the analysis of human peripheral blood T cells. It is highest in CCR7 À CD27 À ''terminally differentiated'' [31,32] In the division of labor between Th cell lineages, Th1 cells are responsible for acute and chronic inflammation and elimination of intracellular pathogens. Since they have to eliminate the cells hosting the pathogens, Th1 cells can also induce considerable immunopathology.…”

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confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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“…In humans, CD27 is expressed on all naive T cells and is markedly up-regulated early after activation [23,24]. However, prolonged and repetitive stimulation of CD27 by CD70 induces down-regulation of the former molecule both in vitro [25] and in vivo [26,27], suggesting that CD27 -T cells are formed as a consequence of extensive receptor triggering.…”

Section: Introductionmentioning

confidence: 99%