Positive selection of T cells, an in vitro view

Dervovic, Dzana; Zúñiga‐Pflücker, Juan Carlos

doi:10.1016/j.smim.2010.04.014

Cited by 27 publications

(19 citation statements)

References 123 publications

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“…In this system, OP9 stromal cells ectopically express the Notch ligand Delta-like 1, which acts in synergy with pre-TCR signals to drive thymocyte differentiation in vitro, including the generation of CD8SP cells (16). To synchronize the initiation of thymocyte development in vitro, we purified DN3 (CD44 − CD25 + ) thymocytes from WT and Gfi1 CD4 mice and cocultured them with OP9-DL1 cells.…”

Section: Cd4mentioning

confidence: 99%

Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes

Shi

Saravia

Kalupahana

et al. 2016

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

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Double-positive (DP) thymocytes respond to intrathymic T-cell receptor (TCR) signals by undergoing positive selection and lineage differentiation into single-positive (SP) mature cells. Concomitant with these well-characterized events is the acquisition of a mature Tcell gene expression program characterized by the induction of the effector molecules IL-7Rα, S1P 1 , and CCR7, but the underlying mechanism remains elusive. We report here that transcription repressor Growth factor independent 1 (Gfi1) orchestrates the fidelity of the DP gene expression program and developmental maturation into SP cells. Loss of Gfi1 resulted in premature induction of effector genes and the transcription factors forkhead box protein O1 (Foxo1) and Klf2 in DP thymocytes and the accumulation of postselection intermediate populations and accelerated transition into SP cells. Strikingly, partial loss of Foxo1 function, but not restored survival fitness, rectified the dysregulated gene expression and thymocyte maturation in Gfi1-deficient mice. Our results establish the Gfi1-Foxo1 axis and the transcriptional circuitry that actively maintain DP identity and shape the proper generation of mature T cells. CD8+ double-positive (DP) stage to mature CD4 + or CD8 + single-positive (SP, namely CD4SP and CD8SP) thymocytes. Whereas the majority of thymocytes are eliminated due to either lack of T-cell receptor (TCR) signals (death by neglect) or high-affinity interaction with self-peptide MHC ligands (negative selection), DP cells with low affinity are rescued from death and undergo positive selection and develop into SP cells. Recent studies have identified a number of transcriptional regulators, such as RARrelated orphan receptor gamma (t) (RORγt), runt-related transcription factor 3 (Runx3), and Th-inducing POZ-kruppel factor (ThPOK), that control positive selection and lineage decision between CD4SP and CD8SP T cells (1-3).In contrast, we have a very limited understanding of the mechanisms underlying the progression of DP into SP cells, a related but rather distinct process from positive selection and CD4/CD8 lineage differentiation (1). Such developmental maturation is characterized by the acquisition of a mature T-cell gene expression program, notably the induction of effector molecules IL-7 receptor α chain (IL-7Rα), C-C motif chemokine receptor 7 (CCR7), and sphingosine 1-phosphate receptor 1 (S1P 1 ) in SP cells that are essential for their proper survival and trafficking (1). Among the few pathways identified to function in DP-to-SP transition, E-proteins play a pivotal role by serving as upstream "sensor" transcription factors in differentiating DP thymocytes (1). E-protein activity in DP thymocytes promotes TCRα gene rearrangement and expression of genes characteristic of immature thymocytes while repressing the expression of effector molecules unique to mature T cells (4). However, given the multifaceted functions of E-proteins in thymocyte selection and survival (5), how E-proteins propagate signals in DP cells is unclear (1). Ther...

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Section: Cd4mentioning

confidence: 99%

Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes

Shi

Saravia

Kalupahana

et al. 2016

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

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“…15,16 The fetal thymic organ culture model and its variants have been invaluable for dissecting the mechanisms of positive selection in vitro. 17 However, these systems are hampered by several technical intricacies and cannot be used for high-throughput studies required to gain further insights into the role of specific peptides and cytokines in positive selection and T-cell differentiation. 17 We have developed a novel in vitro model that is suitable for analysis of positive selection and T-cell differentiation and is based on coculture of CD69 Ϫ DP3 thymocytes with peptide-pulsed OP9 stromal cells and ␥c-cytokines.…”

Section: Introductionmentioning

confidence: 99%

“…17 However, these systems are hampered by several technical intricacies and cannot be used for high-throughput studies required to gain further insights into the role of specific peptides and cytokines in positive selection and T-cell differentiation. 17 We have developed a novel in vitro model that is suitable for analysis of positive selection and T-cell differentiation and is based on coculture of CD69 Ϫ DP3 thymocytes with peptide-pulsed OP9 stromal cells and ␥c-cytokines. This system is simple, flexible, and enables high-throughput analyses of various peptide-cytokine combinations.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of γc cytokines on postselection differentiation of CD8 thymocytes

Rafei

Rouette

Brochu

et al. 2013

Blood

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• We present a novel system for high-throughput analyses of thymocyte selection and differentiation.• We report that IL-4, IL-7, and IL-21 have nonredundant effects on positively selected thymocytes.The primary consequence of positive selection is to render thymocytes responsive to cytokines and chemokines expressed in the thymic medulla. In the present study, our main objective was to discover which cytokines

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“…Although double-positive T cells are a normal part of mature thymocyte development and account for 80% of intrathymic thymocytes, most of them undergo cell death, but normal mature double-positive T cells can persist in healthy patients [24]. The presence of peripheral double-positive T cells has been found in a wide variety of conditions including nodular lymphocyte-predominant Hodgkin lymphoma, classical Hodgkin lymphoma, and progressive transformation of germinal centers [25], as well as autoimmunity [26].…”

Section: Discussionmentioning

confidence: 99%

Utilization of Flow Cytometry in Pediatric Fine-Needle Aspiration Biopsy Specimens

Silowash

Pantanowitz²,

Craig³

et al. 2016

Acta Cytologica

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Background: Fine-needle aspiration (FNA) coupled with flow cytometry (FC) can be helpful in suspicious pediatric lymph nodes or masses to exclude a lymphoproliferative disorder. The aim of this study was to analyze FC findings in a series of pediatric FNAs and to correlate abnormal findings with follow-up information. Materials and Methods: All pediatric FNAs performed at a tertiary-care children's hospital over a 46-month period that had FC performed were retrospectively analyzed and correlated with follow-up. Results: A total of 163 FNA procedures were performed in children (age ≤21 years), and 47 (28.8%) of these cases had FC performed. Specimens were mostly obtained from the head and neck (72.3% of cases). Nine cases (19.1%) had abnormal FC findings, including double-negative T cells (n = 3; 33.3%), double-positive T cells (n = 3; 33.3%), excess λ light chains (n = 1; 11.1%), weak CD34 positivity (n = 1; 11.1%), and T-lymphoblastic lymphoma (n = 1; 11.1%). Conclusion: Unusual FC results that are not diagnostic of malignancy can be seen in lymph node FNA in a minority of young patients. In our series, these findings were seen mainly in small populations of T cells and occurred primarily in the setting of reactive lymphoid hyperplasia or ectopic thymic tissue. Cytopathologists performing FNA on children should be aware of these abnormalities and, although they may warrant further investigation and follow-up, they are unlikely to be associated with malignancy.

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Positive selection of T cells, an in vitro view

Cited by 27 publications

References 123 publications

Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes

Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes

Differential effects of γc cytokines on postselection differentiation of CD8 thymocytes

Utilization of Flow Cytometry in Pediatric Fine-Needle Aspiration Biopsy Specimens

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