Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage

Hendricks, Deborah W.; Fink, Pamela J.

doi:10.1182/blood-2010-07-299263

Cited by 57 publications

(67 citation statements)

References 31 publications

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“…Thus, endowing RTEs with a tendency to die before incorporation into the MN T-cell pool may be a sound evolutionary strategy. Consistent with this idea, RTEs exhibit reduced stimulation-induced proliferation and cytokine production under most conditions (2,21), suggesting that they experience a period of adjustment to the lymphoid periphery before gaining full effector potential. It is possible that some of the cells that die as RTEs are those with inappropriate anti-self specificity, a notion corroborated by evidence that the TCR repertoire is modulated in RTEs (5).…”

Section: Discussionmentioning

confidence: 62%

Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool

Houston¹,

Higdon

Fink³

2011

Proc. Natl. Acad. Sci. U.S.A.

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Recent thymic emigrants (RTEs) are the youngest subset of peripheral T cells, and they differ functionally and phenotypically from the rest of the naïve T-cell pool. RTEs are present in the peripheral T-cell pool throughout life but are the most common subset of T cells in neonates and adults recovering from lymphoablation. Using a murine model to study the homeostasis of RTEs, we show that under lymphoreplete conditions, RTEs are at a competitive disadvantage to already established mature naïve (MN) T cells. This disadvantage may be caused by a defect in survival, because RTEs may transduce homeostatic signals inefficiently, and their ability to survive is enhanced with increased expression of IL-7 receptor or B-cell lymphoma 2 (Bcl-2). Conversely, under lymphopenic conditions, enhanced proliferation by RTEs allows them to out-compete their MN T-cell counterparts. These results suggest that in times of need, such as in neonates or lymphopenic adults, RTEs perform well to fill the gaps in the peripheral T-cell pool, but when the periphery already is full, many RTEs are not incorporated into the pool of recirculating lymphocytes. R ecent thymic emigrants (RTEs) are the youngest subset of naïve T cells, those that recently have entered the lymphoid periphery after development in the thymus. RTEs maintain T-cell diversity in the periphery (1), a particularly important contribution in the very young and in adults recovering from lymphopenia.The original paradigm held that the thymus minted fully functional T cells. However, it is becoming clear that RTEs in both humans and mice undergo postthymic maturation in the lymphoid periphery (2-6) before joining the mature naïve (MN) T-cell pool. RTEs and MN T cells differ in surface phenotype, and, as compared with MN T cells, stimulated RTEs generally proliferate less and secrete less cytokine. Studying RTEs has been facilitated by the characterization of a transgenic (Tg) model system (7) that allows unambiguous identification and live-cell purification of this subset. In mice Tg for GFP under control of the recombination activating gene 2 promoter (RAG2p-GFP Tg mice), RTEs are GFP + peripheral T cells (2). The GFP label is brightest in the youngest RTEs (8) and decays over time until it can no longer be detected on T cells that have been in the lymphoid periphery for more than 3 wk (2).Throughout life, the peripheral T-cell pool is maintained at a relatively constant size despite continuous turnover and thymic export of about 1 × 10 6 cells per day (9, 10). The T-cell pool is maintained at a size large enough to protect adequately against pathogens, with estimated 1 × 10 6 antigen specificities (11), but small enough to avoid taxing the host's resources. Homeostasis is maintained by competition for two limiting factors, IL-7 and MHC loaded with self-peptides (12, 13).Lymphopenia occurs in humans in a variety of clinical and disease settings, including after stem cell transplantation, chemotherapy, and HIV infection. Under lymphopenic conditions, the remaining peripheral ...

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Section: Discussionmentioning

confidence: 62%

Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool

Houston¹,

Higdon

Fink³

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…To test for the potential involvement of DNA methylation changes at these cytokine loci, the HM450 data set was filtered for probes interrogating IL4, IL13, IL2 and IFNG genes. 1,22,23 Clustering and heatmap visualization did not suggest any age-dependent or treatment-dependent effects on methylation at these loci ( Figure 6). …”

Section: Resultsmentioning

confidence: 96%

“…According to the literature, neonatal CD4 þ cells are 'less-mature' recent thymic emigrant phenotypes. 1,22 These have been described as poor at secreting IL-2 under activation conditions and biased toward IL-4 production under non-polarizing conditions compared with later ages. 1,22 This has led to speculation that specific cytokine loci may be subject to distinct epigenetic regulation in neonatal T cells compared with later ages.…”

Section: Resultsmentioning

confidence: 99%

“…1,22 These have been described as poor at secreting IL-2 under activation conditions and biased toward IL-4 production under non-polarizing conditions compared with later ages. 1,22 This has led to speculation that specific cytokine loci may be subject to distinct epigenetic regulation in neonatal T cells compared with later ages. To test for the potential involvement of DNA methylation changes at these cytokine loci, the HM450 data set was filtered for probes interrogating IL4, IL13, IL2 and IFNG genes.…”

Section: Resultsmentioning

confidence: 99%

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Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans

et al. 2012

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The aim of this study was to investigate the dynamics and relationship between DNA methylation and gene expression during early T-cell development. Mononuclear cells were collected at birth and at 12 months from 60 infants and were either activated with anti-CD3 for 24 h or cultured in media alone, and the CD4 þ T-cell subset purified. DNA and RNA were co-harvested and DNA methylation was measured in 450 000 CpG sites in parallel with expression measurements taken from 25 000 genes. In unstimulated cells, we found that a subset of 1188 differentially methylated loci were associated with a change in expression in 599 genes (adjusted P valueo0.01, b-fold 40.1). These genes were enriched in reprogramming regions of the genome known to control pluripotency. In contrast, over 630 genes were induced following low-level T-cell activation, but this was not associated with any significant change in DNA methylation. We conclude that DNA methylation is dynamic during early T-cell development, and has a role in the consolidation of T-cell-specific gene expression. During the early phase of clonal expansion, DNA methylation is stable and therefore appears to be of limited importance in short-term T-cell responsiveness.

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“…For cell sorting, enriched CD4 T cells were obtained using an EasySep Negative Selection Mouse CD4 + T-cell Enrichment Kit (Stem Cell Technologies), surface stained, and sorted using a FACSAria II (Becton Dickinson). Th2-differentiated CD4 T cells were prepared as described previously (55).…”

Section: Methodsmentioning

confidence: 99%

Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions

Higdon

Deets²,

Friesen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Peripheral CD4 T cells in Vβ5 transgenic (Tg) C57BL/6J mice undergo tolerance to an endogenous superantigen encoded by mouse mammary tumor virus 8 (Mtv-8) by either deletion or T-cell receptor (TCR) revision. Revision is a process by which surface expression of the Vβ5 + TCR is down-regulated in response to Mtv-8 and recombination activating genes are expressed to drive rearrangement of the endogenous TCRβ locus, effecting cell rescue through the expression of a newly generated, non-self-reactive TCR. In an effort to identify the microenvironment in which revision takes place, we show here that the proportion of T follicular helper cells (Tfh) and production of high-affinity antibody during a primary response are increased in Vβ5 Tg mice in an Mtv-8-dependent manner. Revising T cells have a Tfh-like surface phenotype and transcription factor profile, with elevated expression of B-cell leukemia/lymphoma 6 (Bcl-6), CXC chemokine receptor 5, programmed death-1, and other Tfh-associated markers. Efficient revision requires Bcl-6 and is inhibited by B lymphocyte-induced maturation protein-1. Revision completes less efficiently in the absence of signaling lymphocytic activation molecule-associated protein although initiation proceeds normally. These data indicate that Tfh formation is required for the initiation of revision and germinal-center interactions for its completion. The germinal center is known to provide a confined space in which B-cell antigen receptors undergo selection. Our data extend the impact of this selective microenvironment into the arena of T cells, suggesting that this fluid structure also provides a regulatory environment in which TCR revision can safely take place.Rag-mediated recombination | T-cell tolerance

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Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage

Cited by 57 publications

References 31 publications

Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool

Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool

Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans

Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions

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