The full spectrum of human naive T cells

Broek, Theo van den; Borghans, José A. M.; Wijk, Femke van

doi:10.1038/s41577-018-0001-y

Cited by 211 publications

(196 citation statements)

References 129 publications

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“…33 T CM cell division forms T E , more daughter T CM , or effector memory T cells (T EM ). 19,20,34 T CM to T EM transition results in the downregulation of CCR7 and CD62L, and a loss in homing ability to lymphoid tissues, although T EM exhibit the highest level of cytotoxicity of all the memory cell subtypes. 19,20,34 Stem cell memory T cells (T SCM ) appear to be a subset of T CM that display a more extensive capacity for selfrenewal.…”

Section: Subsets Of Memory Cellsmentioning

confidence: 99%

“…19,20,34 T CM to T EM transition results in the downregulation of CCR7 and CD62L, and a loss in homing ability to lymphoid tissues, although T EM exhibit the highest level of cytotoxicity of all the memory cell subtypes. 19,20,34 Stem cell memory T cells (T SCM ) appear to be a subset of T CM that display a more extensive capacity for selfrenewal. 19,20,34 Despite their maturity, as determined by TCR excision circle dilution, T SCM share transcription factor profiles, as well as self-renewing characteristic with classic stem cells.…”

Section: Subsets Of Memory Cellsmentioning

confidence: 99%

“…19,20,34 Stem cell memory T cells (T SCM ) appear to be a subset of T CM that display a more extensive capacity for selfrenewal. 19,20,34 Despite their maturity, as determined by TCR excision circle dilution, T SCM share transcription factor profiles, as well as self-renewing characteristic with classic stem cells. 19,20 In adoptive cell immunotherapy, naive, T SCM or T CM subsets outperform T E and T EM , in spite of the enhanced cytotoxic and cytokine-releasing potential of effector T cell subsets.…”

Section: Subsets Of Memory Cellsmentioning

confidence: 99%

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Chimeric antigen receptor T cell persistence and memory cell formation

2019

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It is now becoming clear that less differentiated naive and memory T cells are superior to effector T cells in the transfer of immunity for adoptive cell therapy. This review will outline the challenges faced by chimeric antigen receptor (CAR) T cell therapy in the generation of persistence and memory for CAR T cells, and summarize recent strategies to improve CAR T cell persistence, with a focus on memory cell formation. The relevance of enhancing persistence in more differentiated effector T cells is also covered, because genetic and pharmacological interventions may prolong effector T cell activity and lifespan, thereby improving anti‐cancer activity. In particular, it may be possible to enforce epigenetic changes in differentiated T cells to enhance memory CAR T cell formation. Optimizing the generation of self‐renewing T cell populations (e.g. memory cells), while maintaining differentiated effector T cells through epigenome modification, will help overcome barriers to T cell expansion and survival, thereby improving clinical outcomes in CAR T cell therapy.

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Section: Subsets Of Memory Cellsmentioning

confidence: 99%

Section: Subsets Of Memory Cellsmentioning

confidence: 99%

Section: Subsets Of Memory Cellsmentioning

confidence: 99%

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Chimeric antigen receptor T cell persistence and memory cell formation

2019

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“…To determine the differentiation state of the CD4 + and CD8 + T cells, we stained each subset for CD45RA and CCR7. CD45RA + CCR7 + cells represent naive T cells, CD45RA 2 CCR7 + cells represent central memory T cells, CD45RA 2 CCR7 2 cells represent T-effector/ effector memory T cells, and CD45RA + CCR7 2 cells represent terminally differentiated effector memory CD45RA + T (TEMRA) cells (45,46). In both the CD4 + (Fig.…”

Section: Phenotypic Analysis Of Human T Cells Engrafted In Nsg Nsg-(iamentioning

confidence: 99%

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

et al. 2018

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Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human T‐cell function. However, a major limitation of PBMC engraftment is development of acute xenogeneic graft‐versus‐host disease (GVHD) due to human T‐cell recognition of murine major histocompatibility complex (MHC). To address this, we created 2 NOD‐scid IL‐2 receptor subunit γ (IL2rg)null (NSG) strains that lack murine MHC class I and II [NSG–β‐2‐microglobulin (B2M)null (IA IE)null and NSG‐(Kb Db)null (IAnull)]. We observed rapid human IgG clearance in NSG‐B2Mnull (IA IE)null mice whereas clearance in NSG‐(Kb Db)null (IAnull) mice and NSG mice was comparable. Injection of human PBMCs into both strains enabled long‐term engraftment of human CD4+ and CD8+ T cells without acute GVHD. Engrafted human T‐cell function was documented by rejection of human islet allografts. Administration of human IL‐2 to NSG‐(Kb Db)null (IAnull) mice via adeno‐associated virus vector increased human CD45+ cell engraftment, including an increase in human regulatory T cells. However, high IL‐2 levels also induced the development of GVHD. These data document that NSG mice deficient in murine MHC support studies of human immunity in the absence of acute GVHD and enable evaluation of human antibody therapeutics targeting human T cells.—Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., Shultz, L. D. Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB J. 33, 3137–3151 (2019). http://www.fasebj.org

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“…In order to understand the homeostasis and function of the immune system, further classifications of T cells into subsets including, for example, central and effector memory based on CD62L, CCR7, and other surface markers, regulatory cells based on CD25 and FOXP3, and others, are necessary . Full understanding remains elusive, in part because the distinctions between subsets are seldom clearcut, their origins and possible reversibility are the subject of active research …”

Section: Introductionmentioning

confidence: 99%

Some deterministic and stochastic mathematical models of naïve T‐cell homeostasis

Lythe

Molina-Parı́s

2018

Immunological Reviews

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Humans live for decades, whereas mice live for months. Over these long timescales, naïve T cells die or divide infrequently enough that it makes sense to approximate death and division as instantaneous events. The population of T cells in the body is naturally divided into clonotypes; a clonotype is the set of cells that have identical T-cell receptors. While total numbers of cells, such as naïve CD4 T cells, are large enough that ordinary differential equations are an appropriate starting point for mathematical models, the numbers of cells per clonotype are not. Here, we review a number of basic mathematical models of the maintenance of clonal diversity. As well as deterministic models, we discuss stochastic models that explicitly track the integer number of naïve T cells in many competing clonotypes over the lifetime of a mouse or human, including the effect of waning thymic production. Experimental evaluation of clonal diversity by bulk high-throughput sequencing has many difficulties, but the use of single-cell sequencing is restricted to numbers of cells many orders of magnitude smaller than the total number of T cells in the body. Mathematical questions associated with extrapolating from small samples are therefore key to advances in understanding the diversity of the repertoire of T cells. We conclude with some mathematical models on how to advance in this area.

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The full spectrum of human naive T cells

Cited by 211 publications

References 129 publications

Chimeric antigen receptor T cell persistence and memory cell formation

Chimeric antigen receptor T cell persistence and memory cell formation

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

Some deterministic and stochastic mathematical models of naïve T‐cell homeostasis

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