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The full spectrum of human T naive cells.pdf

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REviEws The full spectrum of human naive T cells Theo van den Broek1,2,3, José A. M. Borghans1 and Femke van Wijk1* Abstract | Naive T cells have long been regarded as a developmentally synchronized and fairly
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  The naive T cell pool is generally considered to be a fairly quiescent, homogeneous pool of antigen- inexperienced cells. However, recent studies have revealed important differences between naive T cells in terms of phenotype, dynamics, differentiation status, location and function. This heterogeneity may be influenced by factors such as age, thymic function and total numbers of T cells and tends to be overlooked in most immunological studies, even though it affects the performance of the immune system. These insights call for a revised view of the naive T cell pool.Although mouse studies have substantially con-tributed to our understanding of the human T cell compartment, the generation, maintenance and func-tion of the naive T cell pool greatly differs between mice and men 1–3 . These differences impose obvious limitations for the extrapolation of insights obtained from mice to humans when trying to understand naive T cell biology, including naive T cell reconsti-tution after lymphopenia , the effects of ageing on the naive T cell compartment and factors important for T cell maintenance.In this Review, we focus on data obtained from humans and review recent findings that expose the  varying levels of heterogeneity in the naive T cell compartment. On the basis of three examples, we discuss the implications of these insights for health and disease. We discuss how reduced immune responses to infection and vaccination in elderly individuals are related to changes in their naive T cell pool. Following this, we cover how similarly reduced immune responses in neonates are related to completely different characteristics of their naive T cell pool. Finally, we argue that immune recovery after haematopoietic stem cell transplantation  (HSCT) needs to be monitored more closely, owing to the slow reconstitution of the naive T cell compartment. What defines a naive T cell? After being subjected to positive and negative selec-tion in the thymus, T cells migrate to the periphery and enter the naive T cell compartment. In the periphery, naive T cells continuously recirculate between sec-ondary lymphoid organs and blood via the lymphatic system by expressing the lymphoid homing receptors CC- chemokine receptor 7 (CCR7) and CD62 ligand (CD62L; also known as L- selectin) (TABLE 1) . In response to encountering and interacting with cognate antigens in the periphery, naive T cells will proliferate and dif-ferentiate into different types of effector and memory T cells, which can migrate to different tissues for local antigen patrol. To ensure adequate immune responses against newly encountered pathogens, the naive T cell compartment must maintain a large number of cells with unique T cell receptors (TCRs) in a limited phys-ical space. This requirement is challenging, because in both humans and mice, the thymus involutes and atrophies with age; homeostatic proliferation  and sur- vival of T cells are thought to compensate for this loss but can lead to the outgrowth of certain T cell clones at the expense of others. Strong indications exist that this challenge is overcome differently in mice and humans. In mice, throughout life, peripheral T cell proliferation hardly contributes to the maintenance of the naive T cell pool. By contrast, the maintenance of the naive T cell pool in human adults is almost entirely depend-ent on peripheral T cell proliferation 1,2 . Furthermore, naive T cells in humans are extremely long- lived, with expected lifespans of 6–9 years, in contrast to those in mice, which are replaced every 6–11 weeks 1,2 . The survival and proliferation of naive T cells is promoted by homeostatic factors, such as IL-7 and self- peptide MHC complexes 4 . Under steady- state conditions, these factors lead to naive T cell pool turnover and mainte-nance, and do not lead to accelerated differentiation of Lymphopenia The condition of having an abnormally low level of lymphocytes in the circulation. Haematopoietic stem cell transplantation (HSCT). Treatment of recipients with irradiation and/or chemotherapy followed by the infusion of cells containing haematopoietic stem and progenitor cells with or without immune cells derived from individuals of the same species. The full spectrum of human naive T cells Theo van den Broek 1,2,3 , José A. M. Borghans 1  and Femke van Wijk 1 * Abstract |  Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation. 1 Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands. 2 Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, Netherlands. 3 Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.*e- mail: F.vanwijk@umcutrecht.nl  https://doi.org/10.1038/ s41577-018-0001-y REVIEWS © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. NATURE REVIEWS |  IMMUNOLOGY  naive T cells towards effector or memory T cell subsets. However, under lymphopenic conditions, the same cues are thought to induce accelerated differentiation 4 . This example illustrates that homeostatic proliferation may have different outcomes in different settings. However, it remains unclear to what extent this proliferation affects the function and dynamic properties of naive T cells.Functionally, T cells are considered naive until they encounter their cognate antigen in the periphery and differentiate into effector or memory T cells. As it is difficult to assess a prior history of antigen recog-nition of T cells in vivo, surface marker expression is commonly used to identify naive T cells. In humans, naive T cells express CD45RA and lack expression of the memory- associated marker CD45RO (TABLE 1) . Expression of at least one extra naive T cell marker (for example, CCR7, CD62L or CD27 (TABLE 1) ) is required to distinguish naive T cells from terminally differen-tiated effector memory T (T EM ) cells, which lack the expression of CCR7, CD62L or CD27 markers but re- express CD45RA (CD45RA +  T EM  cells) 5 . Although dif-ferent laboratories have their own ‘favourite’ naive T cell markers, most of these actually select for highly over-lapping pools of naive T cells. Therefore, in steady- state conditions, a CD45RA + CD45RO –  state in combination with CCR7, CD62L or CD27 expression is sufficient to cover the vast majority of naive T cells while excluding CD45RA +  T EM  cells. However, it is important to realize that this naive T cell identification system will include small populations of functionally distinct T cell subsets, such as forkhead box protein P3 (FOXP3)-expressing regulatory CD4 +  T (T reg ) cells, stem cell memory T (T scm ) cells and memory T cells with a naive phenotype (BOX 1) . Conversely, memory- phenotype T cells that may be antigen- inexperienced, such as virtual memory T cells  and innate memory T cells, are excluded 6 . A system that distinguishes naive T cells on the basis of the lack of expression of transcription factors associated with dif-ferentiation, as discussed below, could be valuable for a stricter definition of naive T cells. It is beyond the scope of this Review to elaborate on all T cell subtypes; how-ever, this illustrates that what is defined as a ‘naive’ T cell strongly depends on the exact definition and context and that, in fact, the naive effector and memory T cell compartments are not so strictly separated. The naive T cell spectrum It has recently become clear that the naive T cell defi-nition covers a whole spectrum of cells with different properties (FIG. 1) ; it is important to appreciate these differences because they may play an important role in clinical settings. Recent thymic emigrants: the youngest naive T cells. Naive T cells that have recently egressed from the thymus are commonly described as recent thymic emigrants (RTEs) 7 . RTEs are functionally different from mature naive T cells   (FIG. 1)  as RTEs show reduced proliferation and cytokine production upon stimula-tion 8 . As the thymus is the only srcin of T cells with new specificities, the RTE population is also the most TCR- diverse part of the naive T cell pool 9 . In itself, the term RTE is confusing because ‘recent’ mostly refers to the immaturity of the naive T cell in terms of lack of prior proliferation and developmental steps and may not be related to the actual age of the cell. Thus, RTEs also form a heterogeneous population of cells with respect to the point in time at which they were released by the thymus.Measuring the contribution of RTEs to the naive T cell pool is not straightforward. A commonly used method is the measurement of T cell receptor excision circles  (TRECs) 1,10–14 . Cell division leads to a decline in the average number of TRECs per T cell, because TRECs are not copied during cell division and are randomly dis-tributed among daughter cells 14–16 . Thus, TRECs do not directly reflect thymus output, and TREC- based analyses of RTEs may be confounded by the presence of TRECs in T cells that have already undergone T cell division. Another disadvantage of using TRECs for the identifi-cation of RTEs is that cells cannot be sorted on the basis of their TREC content, impeding their further analysis.Surface expression of the immunoreceptor tyrosine- based inhibitory motif receptor CD31 (also known as PECAM1; TABLE 1 ) on naive CD4 +  T cells can identify a T cell population that is enriched in RTEs 8,17–20 . CD31 +  naive T cells contain higher TREC levels — suggesting that they have undergone fewer rounds of division — than CD31 –  naive T cells, they have a more diverse TCR repertoire 9  and the percentage of CD31 +  naive T cells declines with age 1,18  and after neonatal thymectomy  21 ; all of these points suggest the usefulness of CD31 as a potential marker for RTEs. However, there are a few limitations of the use of CD31. Following TCR stimu-lation, CD31 expression is downregulated by enzymatic shedding 22 , but it may be re- expressed under specific conditions such as lymphopenia 22 . For CD8 +  RTEs, the association with increased CD31 expression is less clear because CD8 +  T cells ubiquitously express this marker 23 . Instead, CD103 (also known as integrin αE) has been proposed to identify CD8 +  RTEs, as CD8 + CD103 +  naive T cells have a fairly high average TREC content and show a clear age- associated and thymectomy- associated decline 24 . In addition, expression of CD31 on naive CD4 +  T cells does not imply that these cells have never divided. The average TREC content of CD31 +  naive T cells declines with age, which demonstrates that they renew by proliferation, possibly driven by cytokine- induced homeostatic proliferation 19 .Recent findings indeed indicate that there is also heterogeneity within the CD31 +  naive T cell population (FIG. 1) . Expression of protein- tyrosine kinase 7 (PTK7) is associated with CD4 +  RTEs 8  but, in contrast to CD31, is downregulated in vitro upon cytokine- induced pro-liferation without TCR stimulation 8,21 . The production of CXC- chemokine ligand 8 (CXCL8; also known as IL-8) by CD4 +  or CD8 +  naive T cells shows a similar pattern 21,25 . RTEs have long been known to lack or pro-duce only low levels of hallmark effector cytokines such as IFNγ and IL-4 (REFS. 19,25 ) . Gibbons and colleagues were the first to demonstrate that human (and not mouse) naive CD4 +  and CD8 +  T cells have the unique feature of producing IL-8 (REF. 3 ) . IL-8 production is highly enriched in the CD31 + PTK7 +  fraction and is lost within CD31 +  cells following in vitro cytokine- induced Homeostatic proliferation This term can refer to two different phenomena: the steady- state maintenance of T cells through self- renewal (minimal division) and the process by which T cells in lymphopenic conditions rapidly proliferate to reconstitute the T cell pool, also called lymphopenia- induced proliferation.  Virtual memory T cells Antigen- inexperienced memory- phenotype T cells, which may be induced by T cell receptor cross reactivity, low- affinity peptide and/or MHC ligands and certain cytokines. Mature naive T cells Naive T cells that have matured in secondary lymphoid organs following thymic egress and are no longer recent thymic emigrants. T cell receptor excision circles (TRECs). Small, stable circles of DNA excised during T cell receptor gene rearrangement in the thymus. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. www.nature.com/nri REVIEWS  Table 1  |  Surface markers associated with a T cell naive phenotype Marker LigandsExpressionFunction  Refs CD45RA and CD45RO (isoforms of the leukocyte common antigen)UnknownCD45RO is preferentially expressed on memory T cellsCD45 phosphatase activity plays a role in TCR signal transduction, and the SFKs have been identified as its primary targets 113 – 116 CD45RA is expressed on naive T cells and effector memory T cellsCD45RO and CD45RA dual expression occurs when naive T cells differentiate into effector or memory T cells and when T EM  cells re- express CD45RAAs such, exclusion of CD45RO- expressing cells within the CD45RA +  T cell pool is recommended when identifying naive T cell populationsCCR7CCL19 and CCL21CCR7 is expressed at high levels on CD4 +  and CD8 +  naive T cells and T CM  cells but not on T EM  cells and CD45RA +  T EM  cellsCCR7 is involved in the homing of T cells to various secondary lymphoid organs by mediating extravasation via HEVs 5,117 CCR7 and CD45RA co- expression is used to distinguish naive T cells from CD45RA +  T EM  cellsThis is of particular importance for CD8 +  T cells, which show a relatively high proportion of CD45RA +  T EM  cells compared with CD4 +  T cellsCD62LGLYCAM1, CD34 and MADCAM1CD62L is expressed at high levels on CD4 +  and CD8 +  naive and T CM  cells, but T EM  cells show heterogeneous expressionCD62L is a cell adhesion molecule involved in homing of T cells to various secondary lymphoid organs 115,118 – 120 CD62L and CD45RA co- expression is used to distinguish naive T cells from CD45RA +  T EM  cellsThrough rolling adhesion, CD62L decelerates lymphocytes by engaging ligands expressed on HEVsThis is of particular importance for CD8 +  T cells, which show a relatively high proportion of CD45RA +  T EM  cells compared with CD4 +  T cellsCD31CD38, CD31, integrin α v β 3  and glycosaminoglycansCD31 is expressed on naive CD4 +  T cells that have recently egressed from the thymus (for example, RTEs)CD31 has been shown to inhibit TCR signalling in T cells through the action of protein- tyrosine phosphatases (SHIP, SHP1 and SHP2), which are recruited by its immunoreceptor tyrosine- based inhibition motif  18,19,107 ,121 CD31 may be (re-) expressed on memory CD4 +   T cells under specific conditionsCD31 is abundantly expressed by CD8 +  naive T cells; therefore, CD31 expression does not uniquely identify CD8 +  RTEsCD27 (member of the TNFR superfamily)CD70CD27 is expressed by almost all CD4 +  and CD8 +   naive T cellsCD27 plays an important role in T cell and T cell–B cell interactions and provides co- stimulatory signals required for the generation and long- term maintenance of T cell immunity 108,122 – 128 CD27 expression can also be found on CD45RA + CD8 +  T EM  cells and, in conjunction with CD28, is used to identify different CD45RA +  T EM  subsetsCD27 −  T cells arise after long- term antigenic stimulation and indicate a late stage of differentiationCD28CD80 and CD86CD28 is expressed by all naive T cells; however, expression is not limited to naive T cellsCD28 provides co- stimulatory signals required for T cell activation and survival; TCR activation without CD28 co- stimulation results in T cell anergy 108,126,129 – 134 CD28 expression decreases with age, predominantly for CD8 +  T cellsThe lack of CD28 expression on CD8 +   T cells, and to a lesser extent on CD4 +   T cells, is associated with terminal differentiationCD28 expression can be found on CD45RA + CD8 +  T EM  cells and, in conjunction with CD27, is used to identify different CD45RA +  T EM  subsetsThe CD8 + CD28 −  fraction is expanded in elderly individuals as well as in chronic viral infection, malignancies and autoimmunity CCL , CC- chemokine ligand; CCR , CC- chemokine receptor ; CD62L , CD62 ligand; GLYCAM1, putative glycosylation- depended cell adhesion molecule 1; HEVs, high endothelial venules; MADCAM1, mucosal addressin cell adhesion molecule 1; RTEs, recent thymic emigrants; SFKs, Src family of protein tyrosine kinases; SHIP, phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1; SHP1, tyrosine- protein phosphatase non- receptor type 6; SHP2, tyrosine- protein phosphatase non- receptor type 11; T CM  cell, central memory T cell; TCR , T cell receptor ; T EM  cell, effector memory T cell; TNFR , tumour necrosis factor receptor . © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. NATURE REVIEWS |  IMMUNOLOGY REVIEWS  proliferation and following neonatal thymectomy  21 . Interestingly, although IL-8 expression is imprinted early during thymic selection, IL-8 expression is relatively low in mature single- positive thymocytes in contrast to PTK7 expression, which is already high in mature single- positive thymocytes 21,25 . It remains to be elucidated whether IL-8 production is induced extrathymically or whether naive T cells that are about to egress from the thymus upregulate IL-8. Recently, it was shown that the most immature RTE fraction is also enriched for complement receptor type 1 (CR1) and CR2 expres-sion 26 . Together, PTK7, IL-8, CR1 and CR2 seem to identify the least- differentiated RTEs. Naive T cell maturation and differentiation. RTEs are thought to undergo maturation in secondary lym-phoid organs before they gain full functional compe-tency. Mature naive T cells show higher proliferation, cytokine production and expression of early activation markers (including CD25) upon antigen encounter than RTEs 27 . In humans, CD25 dim  naive T cells show signs of prior activation, as they have lower expression of CD45RA and higher expression of the intracellular proliferation marker Ki-67 than CD25 −  naive T cells. Although their TREC content is lower than that of CD25 −  naive T cells, CD25 dim  naive T cells still show a broad TCR Vβ repertoire 28,29 , which suggests that they are not very far along the T cell differentiation pathway.Although the signals that drive RTE maturation are largely unknown, the route of T cell differentiation may be metabolically and epigenetically regulated 30–32 . Epigenetic mechanisms — including DNA methylation, histone mod-ifications and non- coding RNAs — regulate rearrange-ment of chromatin to promote or prevent gene expression. The chromatin accessibility landscape has been shown to differ greatly between naive and memory T cells 33,34 . Human naive CD8 +  T cells were found to have increased accessibility and expression of transcription factors related to, for example, TCR signalling, whereas memory CD8 +  T cells exhibit greater accessibility and expression of tran-scription factors related to T cell differentiation and effec-tor function 34 . For human CD4 +  T cell differentiation, a progressive loss of DNA methylation from naive T cells to central memory T (T CM ), T EM  and CD45RA +  T EM  cells has been observed. In addition, FOXP1 has been proposed as a candidate gatekeeper transcription factor of CD4 +  T cell ‘naivety’ 33 . Although these data clearly show that naive T cells have reduced expression and accessibility of transcription factors that are associated with differentia-tion compared with memory T cells 33,34 , little is known as yet about differences within the naive T cell compartment. Recent studies in mice, which show that RTEs and mature naive T cells exhibit differential DNA methylation levels at key cytokine ( Il2  and Il4 ) loci, suggest that epigenetic regulation also acts as a mechanistic basis for post- thymic naive T cell maturation 30 . Box 1 |  Naive- like T cells Regulatory T cells Regulatory CD4 +  T (T reg ) cells represent a specific lineage that plays a crucial role in the maintenance of self- tolerance and immune homeostasis 88,89 . Although T reg  cells can be induced in the periphery, the majority of circulating T reg  cells are generated in the thymus. T cells are thought to adopt a T reg  programme in the thymus when they have a higher T cell receptor (TCR) affinity for a self- peptide than non- T reg  CD4 +  T cells 90,91 , and T reg  differentiation is further dependent on both IL-2 and IL-15 (REF. 92 ) . T reg  cells that exit the thymus express classical naive T cell markers, including CD45RA, CC- chemokine receptor 7 (CCR7) and CD62 ligand (CD62L), but, in contrast to conventional naive T cells, express relatively low levels of IL-7 receptor- α  (CD127). When assessing the conventional naive CD4 +  T cell compartment, T reg  cells can be excluded based on forkhead box protein P3 (FOXP3) and/or CD25 expression in combination with low CD127 expression 93 . Stem cell memory T cells Within the CD45RA + CCR7 + CD4 +  or CD8 +  T cell compartments, a proportion of T cells are distinct from truly naive T cells as they show phenotypical and functional characteristics reminiscent of effector and memory T cells. Among these naive- like memory T cells, a subset termed stem cell memory T (T scm ) cells is characterized by the expression of CD95, CD122, CXC- chemokine receptor 3 (CXCR3) and the integrin CD11a ( β 2  integrin subunit of LFA1) 94– 97 . These cells express a substantially lower T cell receptor excision circle (TREC) content than the naive T cell population as a whole, similar to non- naive T cells, and can rapidly acquire effector functions upon antigenic and homeostatic stimulation. Despite low TREC levels, high expression levels of the intracellular proliferation marker Ki-67 and a restricted TCR repertoire 98  (all characteristics that suggest that they have undergone several rounds of division), T scm  cells maintain their naive- like phenotype. These cells have stem- cell-like properties of self- renewal, can persist for decades 94– 97  and are maintained by extensive proliferation 97   (FIG. 1) . Memory T cells with a naive phenotype Another naive- like memory subset of CD8 +  T cells was recently identified that shows high expression of CXCR3 and CD49d, high IFN γ  production and high T- box transcription factor TBX21 expression but that phenotypically and transcriptionally differed from characteristic memory and effector T cells 99 . Although naive- like memory T cells show similar telomere lengths to naive T cells, CD8 +  naive- like memory T cells have a restricted TCR V β  repertoire, suggesting that these cells underwent antigen- driven expansion 99 . RNA sequencing analysis placed CD8 +  naive- like memory T cells in between naive and central memory T cells, similar to T scm  cells 99 . Whereas CXCR3 expression is similar for these two naive- like memory T cell populations, naive- like memory T cells and T scm  cells differ phenotypically in terms of CD95, CD122 and CD11a expression 99 . Although naive- like memory T cells phenotypically appear as naive T cells, the current view is that because they are antigen- experienced they should be considered as the least differentiated stage of the memory T cell pool and not be incorporated within the naive T cell compartment. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. www.nature.com/nri REVIEWS

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Mar 27, 2018

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