Asymmetric T Lymphocyte Division in the Initiation of Adaptive Immune Responses

Chang, John T.; Palanivel, V.; Kinjyo, Ichiko; Schambach, Felix; Intlekofer, Andrew M.; Banerjee, Arnob; Longworth, Sarah; Vinup, Kristine E.; Mrass, Paulus; Oliaro, Jane; Killeen, Nigel; Orange, Jordan S.; Russell, Sarah M.; Weninger, Wolfgang; Reiner, Steven L.

doi:10.1126/science.1139393

Cited by 753 publications

(951 citation statements)

References 40 publications

(62 reference statements)

Supporting

Mentioning

882

Contrasting

Unclassified

Order By: Relevance

“…During the past several years two broad and contrasting models have emerged to explain how memory CD8 T cells retain both naïve and effector features. One model describes effector and memory differentiation as distinct lineages arising from asymmetric cell division of the original naïve T cell, allowing memory T cells to retain gene expression programs from the naïve parental cell 2,20,21 . A contrasting model describes memory T cell differentiation as a process whereby memory CD8 T cells arise from a subset of effector cells (MP cells) that have the ability to re-acquire key naïve-like properties such as homing to lymphoid tissues but still retain the ability to rapidly elaborate effector functions 2,22 .…”

mentioning

confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

381

359

View full text Add to dashboard Cite

Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These resting memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogen, but also have many properties in common with naïve cells, including the ability to migrate to lymph nodes and spleen, and their pluri-potency. Thus, memory cells embody features of both naïve and effector cells, fueling a long-standing debate centered on whether memory T cells develop from effector cells or directly from naïve cells1–4. To better define the developmental path of memory CD8 T cells we investigated changes in DNA methylation programming at naïve and effector genes in virus specific CD8 T cells during acute LCMV infection of mice. Methylation profiling of effector CD8 T cell subsets at day 4 and 8 after infection showed that, rather than retaining a naïve epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naïve-associated genes and became demethylated at loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase, Dnmt3a, at an early stage of effector differentiation strikingly reduced methylation of naïve-associated genes and resulted in faster re-expression of these naïve genes, accelerating memory cell development. Longitudinal phenotypic and epigenetic characterization of virus-specific memory-precursor CD8 T cells transferred into antigen-free mice revealed that their differentiation into memory cells was coupled to cell-division independent erasure of de novo methylation programs and re-expression of naïve-associated genes. These data provide evidence that epigenetic repression of naïve-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells supporting a differentiation model where memory T cells arise from a subset of fate-permissive effector T cells.

show abstract

mentioning

confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

381

359

View full text Add to dashboard Cite

show abstract

“…T cell-APC interactions have been studied dynamically in vitro and components of the molecular structures that comprise the synapse have been elegantly characterized [1,2,3]. More recently in vivo documentation of T cell and APC trafficking and interactions have been documented, especially through the use of two photon confocal microscopy [4,5,6,7,8,9].…”

Section: Introductionmentioning

confidence: 99%

T cell–antigen-presenting cell interactions visualized in vivo in a model of antigen-specific inflammation

Rosenbaum

Ronick

Song

et al. 2008

Clinical Immunology

View full text Add to dashboard Cite

Videomicroscopy is being used increasingly to characterize the interaction of T cells and antigenpresenting cells (APCs) within lymphatic tissues but has not been reported, to our knowledge, at sites of inflammation. We employed intravital videomicroscopy to study an anterior uveitis model using DO11.10 T cells and ovalbumin (OVA). T cell movement in iris was consistent with a random walk independent of the presence of recognized antigen and had a lateral speed slower than T cells in lymph node. Lingering of T cells adjacent to APCs suggested that they were physically interacting. This apparent contact demonstrated antigen specificity when comparing results from DO11.10 cells with OVA versus bovine serum albumin (BSA) loaded APCs but not when comparing results from OVA-loaded APCs with DO11.10 versus HA clonotype 6.5 T cells. Further studies with this model system should clarify the contribution of T cell-APC communication at a site of inflammation, infection, or immunization.

show abstract

“…For example, ex vivo imaging of cells stimulated in vivo has demonstrated asymmetric division events that may provide a basis for the development of heterogeneity [9]. Eventually these powerful techniques may allow the fates of single cells and their offspring to be followed over extended periods.…”

mentioning

confidence: 99%

Modelling pathways of CD8⁺ T‐cell differentiation

Yates¹

2009

Eur J Immunol

View full text Add to dashboard Cite

In an immune response to infection, naïve T lymphocytes proliferate and give rise to a heterogeneous population of effector and memory cells. How is this diversity generated, and how can it be manipulated? Answering these questions requires an understanding of the lineage relationships between different effector and memory-cell subsets, but these relationships remain to be identified definitively. In this issue of the European Journal of Immunology, a study moves us closer to this goal by combining a mathematical model and data from influenza infections in mice to support the hypothesis that CD8 1 T-cell differentiation is strongly coupled to cell division.Key words: CD8 T cell . Differentiation . Mathematical modelling See accompanying article by Schlub et al.A textbook depiction of a CD8 1 T-cell response involves clonal expansion, contraction and memory formation. This familiar dynamic arises from a complex set of developmental processes. The responding population usually comprises multiple TCR specificities and rapidly exhibits a diverse range of effector functions, migratory patterns and potential for long-term persistence as memory cells. Understanding how this heterogeneity develops and how it might be manipulated has important consequences for vaccine design.The diversity of the CD8 1 T-cell response in vivo can arise from a single naïve antigen-specific precursor [1]. This observation directly challenges ''one cell, one fate'' models of the development of heterogeneity in T-cell responses, in which multiple naïve precursor cells are either pre-disposed to different fates or receive distinct instructional signals from Ag-presenting cells at the priming stage. Thus, the diversity appears to be generated progressively during clonal expansion -but how?There exists a wealth of beautiful experimental studies dissecting the factors that influence the clonal and phenotypic structure of T-cell responses, such as signal strength and co-stimulation [2], Ag persistence [3], the timing of viral epitope presentation [4], precursor frequency [5,6] and inflammation [7]. However, a consistent picture of the rules underlying the development of heterogeneity in T-cell responses has been elusive, partly due to difficulties in isolating and controlling the many factors that influence these responses in vivo. In addition, understanding how diversity arises requires knowledge of cells' ancestries, and there are significant (but diminishing) technical barriers to tracking cell fates during immune responses. For example, adoptive transfer of CFSE-labelled cells provides a tool for observing correlations between division number and differentiation, but proliferation rapidly dilutes the label to undetectable levels and so restricts such analyses to short temporal windows [8]. Furthermore, adoptive transfer experiments often utilise unphysiologically high precursor cell numbers, which can limit the extent of clonal expansion and distort the patterns of differentiation observed in endogenous responses [5].Recent advances in multi p...

show abstract

Asymmetric T Lymphocyte Division in the Initiation of Adaptive Immune Responses

Cited by 753 publications

References 40 publications

Effector CD8 T cells dedifferentiate into long-lived memory cells

Effector CD8 T cells dedifferentiate into long-lived memory cells

T cell–antigen-presenting cell interactions visualized in vivo in a model of antigen-specific inflammation

Modelling pathways of CD8⁺ T‐cell differentiation

Contact Info

Product

Resources

About

Asymmetric T Lymphocyte Division in the Initiation of Adaptive Immune Responses

Cited by 753 publications

References 40 publications

Effector CD8 T cells dedifferentiate into long-lived memory cells

Effector CD8 T cells dedifferentiate into long-lived memory cells

T cell–antigen-presenting cell interactions visualized in vivo in a model of antigen-specific inflammation

Modelling pathways of CD8+ T‐cell differentiation

Contact Info

Product

Resources

About

Modelling pathways of CD8⁺ T‐cell differentiation