Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen

Pircher, Hanspeter; Bürki, Kurt; Lang, Rosemarie; Hengartner, Hans; Zinkernagel, Rolf M.

doi:10.1038/342559a0

Cited by 939 publications

(783 citation statements)

References 22 publications

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“…These findings contrast with data obtained with rather higher affinity TCR, such as the 318 or 2C transgenic TCR [28,29]. In 318 TCR transgenic mice with exclusively selecting (H-2 bb ) or heterozygous H-2 haplotype (H-2 bd , H-2 bk or H-2 bq ), the percentage of peripheral CD8 + cells expressing transgenic TCR always remained above 50% independent of reduced TCR-restricting H-2D b density and independent of the presence of a thymic environment ( [14] and unpublished data).…”

Section: Discussioncontrasting

confidence: 99%

Role of TCR‐restricting MHC density and thymic environment on selection and survival of cells expressing low‐affinity T cell receptors

et al. 2004

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H-Y-specific T cell receptor (TCR) transgenic mice express an MHC class I H-2D b -restricted TCR specific for a male antigen-derived peptide (H-Y). Selection and survival of cells expressing this low-affinity TCR were analyzed under optimal and sub-optimal conditions. Optimal conditions were provided by a thymic environment with high H-2D b density. Suboptimal conditions were provided by a thymic environment with decreased H-2D b density or by an athymic environment with either high or low H-2D b density. Whereas negative selection was still guaranteed under sub-optimal conditions, selection and survival efficiency of cells expressing the transgenic TCR were strongly dependent on optimal conditions. These results indicated that both a thymic microenvironment and a high density of TCR-restricting MHC molecules were needed to ensure selection and maintenance of cells expressing TCR with low affinity and hence a more diverse T cell repertoire.

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Section: Discussioncontrasting

confidence: 99%

Role of TCR‐restricting MHC density and thymic environment on selection and survival of cells expressing low‐affinity T cell receptors

et al. 2004

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“…Congenically marked LCMV-specific CD8 T cells were sorted using fluorescently labeled CD90.1 (Thy1.1) and CD8 antibodies as previously described 14 . Naïve antigen-specific cells obtained from transgenic P14 mice 30 were used as an antigen-specific naïve control. Dnmt3a conditional knockout mice were generated by breeding previously characterized floxed Dnmt3a mice with mice that contain a granzyme b driven recombinase transgene 17,31 .…”

Section: Methodsmentioning

confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

402

359

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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.

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“…Hence, we assessed the capacity of DC at various activation stages to induce polarization of a transgenic T cell population with a different specificity, i.e. cells from TCR7 mice expressing a TCR specific for the epitope 33-41 of lymphocytic choriomeningitis virus (LCMV) glycoprotein 1 (gp [33][34][35][36][37][38][39][40][41] ) [37,38]. In this set of experiments we also tested CpG as pro-maturation stimulus (see Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…DO11.10 mice express a Tg ab TCR specific for OVA 323-339 presented in the context of I-A d molecules. LCMV gp33 mice, which express a TCR specific for gp [33][34][35][36][37][38][39][40][41] in association with H-2D b [37], were backcrossed onto C57BL/6 background over six generations to obtain TCR7 mice [38]. All mice were housed in a specific pathogen-free animal facility, and treated in accordance with the European Union Guidelines together with the approval of the Institutional Ethics Committee.…”

Section: Discussionmentioning

confidence: 99%

“…Single-cell suspensions (1Â10 6 cells/mL) of spleen and lymph nodes cells from OT-1 or TCR7 mice were seeded into 6-well plates together with different populations of DC (ratio 5:1; see below) loaded with 100 nM SIINFEKL peptide [34] or 10 nM gp [33][34][35][36][37][38][39][40][41] (Research Genetics, Huntsville, AL) in RPMI 1640 supplemented with penicillin/streptomycin, 10 mM HEPES, 10 mM Na-pyruvate, 50 lM 2-mercaptoethanol and 10% heatinactivated FCS. In order to obtain highly polarized Tc1 or Tc2 cells, IL-12 (3.5 ng/mL) or IL-4 (5 ng/mL; R&D Systems, Minneapolis, MN), respectively, was added to the cultures.…”

Section: Generation and Functional Characterization Of Tc1 And Tc2 Cementioning

confidence: 99%

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Prolonged exposure of dendritic cells to maturation stimuli favors the induction of type‐2 cytotoxic T lymphocytes

Boni¹,

Iezzi

Degl’Innocenti³

et al. 2006

Eur J Immunol

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Dendritic cell (DC) maturation influences the priming and polarization of T lymphocytes. We recently found that early activated DC (i.e. DC exposed to promaturation stimuli for 8 h) were more prone to prime in vivo a type-1 cytotoxic T cell (Tc1) response than DC exposed to pro-maturation stimuli for 48 h (48h-DC). We investigated whether 48h-DC, conversely, allowed the induction of Tc2 cells. Antigenpulsed mouse bone-marrow-derived DC at any maturation stage, in the presence of exogenous IL-12, skewed in vitro naive CD8 + T cells towards Tc1 cells, but 48h-DC most potently, in the presence of exogenous IL-4, favored the induction of Tc2 cells. In vivo, full maturation of DC promoted expansion of Tc2 and fall of Tc1 cells. Tc2 cells maintained a high cytolytic activity and produced significant amounts of IL-4, IL-5, IL-10 and TGF-b. Our results indicate that polarization of naive CD8 + T cells to Tc2 cells is dependent on the amount of time DC have been exposed to maturation stimuli, and might be favored in late and/or chronic phases of an immune response.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35597_s.pdf IntroductionUpon antigenic stimulation, T lymphocytes proliferate and acquire a variety of effector functions. Indeed, activation of naive CD4 + T cells in the presence of IL-12 results in the development of Th1 cells, which mainly secrete interferon (IFN)-c, interleukin (IL)-2, tumor necrosis factor (TNF)-a and lymphotoxin, and are commonly associated with a cell-mediated immune response. Conversely, the presence of IL-4 skews the Th response towards Th2 cells producing IL-4, IL-10 and IL-13, relevant cytokines against helminthiasis and allergic diseases [1]. More recently, a third subset of CD4 + T cells has been identified, which express CD25, produce IL-10 and TGF-b, and display regulatory functions [2].The polarization of CD8 + CTL has been less characterized [3]. IL-12 also appears to be critical for the generation of Tc1 cells, characterized by a high production level of IFN-c and cytolytic activity, CC chemokine receptor (CCR)5 expression and the ability to migrate to the inflamed tissues where they are [16], and in many cases their presence was associated with disease severity and progression [13][14][15][16]. In mouse tumor models, IL-4-transduced tumor cells elicited potent antitumor activities [17] and induced Tc2 cells able to cure lung metastases [5,17]. IL-4 produced by CTL was required for the generation of protective tumor-associated CD8 + T cells [5,18]. In other models, Tc2 cells were far less effective in curing subcutaneous tumors [19,20] and lung metastases [21]. Finally, CD8 + T cell subpopulations exhibiting regulatory function have also been described [14,22].Dendritic cells (DC), professional antigen presenting cells (APC) with a unique ability in priming T cell responses [23], play a key role in T cell polarization. In particular, it has been reported that subsets of DC, derived from distinct precursors, induce differenti...

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Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen

Cited by 939 publications

References 22 publications

Role of TCR‐restricting MHC density and thymic environment on selection and survival of cells expressing low‐affinity T cell receptors

Role of TCR‐restricting MHC density and thymic environment on selection and survival of cells expressing low‐affinity T cell receptors

Effector CD8 T cells dedifferentiate into long-lived memory cells

Prolonged exposure of dendritic cells to maturation stimuli favors the induction of type‐2 cytotoxic T lymphocytes

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