Constitutive Expression of MEF2C, LYL1, or LMO2 in CD34+ HSCs Blocks the in Vitro Differentiation before the T-Cell Commitment Point and Could be Oncogenic in Early T-Cell Progenitor ALL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2423-2423
Author(s):  
Kirsten Canté-Barrett ◽  
Rui D Mendes ◽  
Wilco K Smits ◽  
Rob Pieters ◽  
Jules PP Meijerink
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Cell Commitment

Abstract Background: T-cell development in the thymus is a complex process that depends on sequential transcriptional and epigenetic events that induce T-cell lineage commitment and simultaneously suppress alternative cell fates. In T-cell acute lymphoblastic leukemia (T-ALL), aberrantly expressed oncogenes result in the arrest of developing thymocytes, which can lead to the acquisition of secondary mutations, uncontrolled proliferation and disease progression. MEF2C is often expressed as a result of chromosomal rearrangements in immature, early T-cell progenitor ALL (ETP-ALL), but is also expressed in normal thymocyte progenitors before T-cell commitment (in the ETP stage). As the only hematopoietic lineage, thymocytes that have passed the T-cell commitment checkpoint (as well as mature T-cells) do no longer express MEF2C. Aims: We aimed to investigate the effect of constitutive MEF2C expression on early T-cell development. OP9-DL1 co-cultures have been most useful for mimicking in vitro T-cell development starting with hematopoietic stem cells (HSCs) derived from human cord blood or bone marrow. We also aimed to investigate the impact of MEF2C in comparison to LYL1 and LMO2; two T-ALL oncogenes also highly expressed at the ETP stage. Methods: We have utilized the OP9-DL1 in vitro co-culture system to gradually differentiate CD34+ HSCs from umbilical cord blood into the T-cell lineage. HSCs in this co-culture will recapitulate in vivo T-cell development as measured by incremental acquisition of surface markers CD7, CD5, CD1a, and reach the CD4, CD8 double-positive (DP) stage. We generated gene expression profiles of 11 subsequent in vitro stages of differentiation to help us match them to in vivo development stages. We investigated in vitro T-cell differentiation of HSCs after lentiviral transduction with MEF2C or control vectors, as well as with other transcriptional regulators LYL1 and LMO2 that are expressed at the ETP stage. Results: The major change in gene expression of subsequent early T-cell differentiation stages defines two distinct T-cell differentiation clusters that correlate with in vivo pre- and post-T-cell commitment profiles. We found that T-cell commitment occurs in CD7+ CD5+ cells before the acquisition of CD1a surface expression. Expression of control vectors in HSCs does not affect the in vitro T-cell differentiation, but MEF2C expression blocks differentiation into the direction of T-cells as measured by the failure of most cells to acquire CD7 as the first marker. Instead, with increased passage number cells gradually lose CD34 expression and eventually disappear from the co-culture. Similar effects were observed for the expression of LYL1 and LMO2; LYL1 expression arrests the cells at the most immature CD7+ ETP stage and prevents the transition towards CD7+ CD5+ cells, whereas LMO2 expressing cells reach the CD7+ CD5+ stage but fail to acquire CD1a as a marker of T-cell commitment. Summary/Conclusion: The gene expression profiles of 11 human in vitro T-cell differentiation subsets has enabled us to pinpoint T-cell commitment to a stage in which cells have acquired CD7 and CD5, just prior to the acquisition of CD1a. MEF2C, LYL1, and LMO2, expressed in ETP-ALL as well as in normal thymocyte progenitors, do not allow the transition to T-cell commitment when constitutively expressed. These proteins each result in the arrest of in vitro differentiating T-cells at different ETP stages, all before the T-cell commitment as marked by CD1a expression. Constitutive expression of MEF2C, LYL1, or LMO2 in very early thymocyte progenitors is incompatible with development into and beyond the T-cell commitment checkpoint and these proteins could therefore play important roles in the pathogenesis of ETP-ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Analysis of Thymocyte Development Reveals That the Gtpase Rhoa Is a Positive Regulator of T Cell Receptor Responses in Vivo

2001 ◽  
Vol 194 (7) ◽  
pp. 903-914 ◽  
Author(s):  
Isabelle Corre ◽  
Manuel Gomez ◽  
Susina Vielkind ◽  
Doreen A. Cantrell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Thymocyte Development

Loss of function of the guanine nucleotide binding protein RhoA blocks pre-T cell differentiation and survival indicating that this GTPase is a critical signaling molecule during early thymocyte development. Previous work has shown that the Rho family GTPase Rac-1 can initiate changes in actin dynamics necessary and sufficient for pre-T cell development. The present data now show that Rac-1 actions in pre-T cells require Rho function but that RhoA cannot substitute for Rac-1 and induce the actin cytoskeletal changes necessary for pre-T cell development. Activation of Rho is thus not sufficient to induce pre-T cell differentiation or survival in the absence of the pre-T cell receptor (TCR). The failure of RhoA activation to impact on pre-TCR–mediated signaling was in marked contrast to its actions on T cell responses mediated by the mature TCR α/β complex. Cells expressing active RhoA were thus hyperresponsive in the context of TCR-induced proliferation in vitro and in vivo showed augmented positive selection of thymocytes expressing defined TCR complexes. This reveals that RhoA function is not only important for pre-T cells but also plays a role in determining the fate of mature T cells.

T-cell generation by lymph node resident progenitor cells

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 193-200 ◽  
Author(s):  
Rafik Terra ◽  
Isabelle Louis ◽  
Richard Le Blanc ◽  
Sophie Ouellet ◽  
Juan Carlos Zúñiga-Pflücker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Stromal Cells ◽  
Integration Site ◽  
T Cell Development ◽  
Cell Development ◽  
Lymphoid Organ ◽  
Oncostatin M ◽  
Cell Commitment

In the thymus, 2 types of Lin–Sca-1+ (lineage-negative stem cell antigen-1–positive) progenitors can generate T-lineage cells: c-Kithi interleukin-7 receptor α–negative (c-KithiIL-7Rα–) and c-KitloIL-7Rα+. While c-KithiIL-7Rα– progenitors are absent, c-KitloIL-7Rα+ progenitors are abundant in the lymph nodes (LNs). c-KitloIL-7Rα+ progenitors undergo abortive T-cell commitment in the LNs and become arrested in the G1 phase of the cell cycle because they fail both to up-regulate c-myb, c-myc, and cyclin D2 and to repress junB, p16INK4a, and p21Cip1/WAF. As a result, development of LN c-KitloIL-7Rα+ progenitors is blocked at an intermediate CD44+CD25lo development stage in vivo, and LN-derived progenitors fail to generate mature T cells when cultured with OP9-DL1 stromal cells. LN stroma can provide key signals for T-cell development including IL-7, Kit ligand, and Delta-like–1 but lacks Wnt4 and Wnt7b transcripts. LN c-KitloIL-7Rα+ progenitors are able to generate mature T cells when cultured with stromal cells producing wingless-related MMTV integration site 4 (Wnt4) or upon in vivo exposure to oncostatin M whose signaling pathway intersects with Wnt. Thus, supplying Wnt signals to c-KitloIL-7Rα+ progenitors may be sufficient to transform the LN into a primary T-lymphoid organ. These data provide unique insights into the essence of a primary T-lymphoid organ and into how a cryptic extrathymic T-cell development pathway can be amplified.

Induction of T-cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1431-1439 ◽  
Author(s):  
Ross N. La Motte-Mohs ◽  
Elaine Herer ◽  
Juan Carlos Zúñiga-Pflücker
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cord Blood ◽  
T Cell Development ◽  
T Cell Differentiation ◽  
Human Cord Blood ◽  
Hematopoietic Stem

AbstractThe Notch signaling pathway plays a key role at several stages of T-lymphocyte differentiation. However, it remained unclear whether signals induced by the Notch ligand Delta-like 1 could support full T-cell differentiation from a defined source of human hematopoietic stem cells (HSCs) in vitro. Here, we show that human cord blood–derived HSCs cultured on Delta-like 1–expressing OP9 stromal cells undergo efficient T-cell lineage commitment and sustained T-cell differentiation. A normal stage-specific program of T-cell development was observed, including the generation of CD4 and CD8 αβ–T-cell receptor (TCR)–bearing cells. Induction of T-cell differentiation was dependent on the expression of Delta-like 1 by the OP9 cells. Stimulation of the in vitro–differentiated T cells by TCR engagement induced the expression of T-cell activation markers and costimulatory receptors. These results establish an efficient in vitro coculture system for the generation of T cells from human HSCs, providing a new avenue for the study of early T-cell differentiation and function.

scholarly journals CD69 Association with Jak3/Stat5 Proteins Regulates Th17 Cell Differentiation

2010 ◽  
Vol 30 (20) ◽  
pp. 4877-4889 ◽  
Author(s):  
Pilar Martín ◽  
Manuel Gómez ◽  
Amalia Lamana ◽  
Arantxa Cruz-Adalia ◽  
Marta Ramírez-Huesca ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Th17 Cells ◽  
T Cell Differentiation ◽  
Orphan Receptor ◽  
Interleukin 17 ◽  
Deficient Mice

ABSTRACT T-cell differentiation involves the early decision to commit to a particular pattern of response to an antigen. Here, we show that the leukocyte activation antigen CD69 limits differentiation into proinflammatory helper T cells (Th17 cells). Upon antigen stimulation in vitro, CD4+ T cells from CD69-deficient mice generate an expansion of Th17 cells and the induction of greater mRNA expression of interleukin 17 (IL-17), IL 23 receptor (IL-23R), and the nuclear receptor retinoic acid-related orphan receptor γt (RORγt). In vivo studies with CD69-deficient mice bearing OTII T-cell receptors (TCRs) specific for OVA peptide showed a high proportion of antigen-specific Th17 subpopulation in the draining lymph nodes, as well as in CD69-deficient mice immunized with type II collagen. Biochemical analysis demonstrated that the CD69 cytoplasmic tail associates with the Jak3/Stat5 signaling pathway, which regulates the transcription of RORγt and, consequently, differentiation toward the Th17 lineage. Functional experiments in Th17 cultures demonstrated that the selective inhibition of Jak3 activation enhanced the transcription of RORγt. Moreover, the addition of exogenous IL-2 restored Stat5 phosphorylation and inhibited the enhanced Th17 differentiation in CD69-deficient cells. These results support the early activation receptor CD69 as an intrinsic modulator of the T-cell differentiation program that conditions immune inflammatory processes.

scholarly journals Hierarchy of Notch–Delta interactions promoting T cell lineage commitment and maturation

2007 ◽  
Vol 204 (2) ◽  
pp. 331-343 ◽  
Author(s):  
Valerie Besseyrias ◽  
Emma Fiorini ◽  
Lothar J. Strobl ◽  
Ursula Zimber-Strobl ◽  
Alexis Dumortier ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Lineage Commitment ◽  
Binding Studies ◽  
Maturation In Vitro ◽  
Cell Commitment

Notch1 (N1) receptor signaling is essential and sufficient for T cell development, and recently developed in vitro culture systems point to members of the Delta family as being the physiological N1 ligands. We explored the ability of Delta1 (DL1) and DL4 to induce T cell lineage commitment and/or maturation in vitro and in vivo from bone marrow (BM) precursors conditionally gene targeted for N1 and/or N2. In vitro DL1 can trigger T cell lineage commitment via either N1 or N2. N1- or N2-mediated T cell lineage commitment can also occur in the spleen after short-term BM transplantation. However, N2–DL1–mediated signaling does not allow further T cell maturation beyond the CD25+ stage due to a lack of T cell receptor β expression. In contrast to DL1, DL4 induces and supports T cell commitment and maturation in vitro and in vivo exclusively via specific interaction with N1. Moreover, comparative binding studies show preferential interaction of DL4 with N1, whereas binding of DL1 to N1 is weak. Interestingly, preferential N1–DL4 binding reflects reduced dependence of this interaction on Lunatic fringe, a glycosyl transferase that generally enhances the avidity of Notch receptors for Delta ligands. Collectively, our results establish a hierarchy of Notch–Delta interactions in which N1–DL4 exhibits the greatest capacity to induce and support T cell development.

scholarly journals B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation

2018 ◽  
Vol 215 (9) ◽  
pp. 2429-2443 ◽  
Author(s):  
Mark D. Singh ◽  
Minjian Ni ◽  
Jenna M. Sullivan ◽  
Jessica A. Hamerman ◽  
Daniel J. Campbell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Pi3k Signaling ◽  
Memory T Cell

CD8+ T cells respond to signals via the T cell receptor (TCR), costimulatory molecules, and immunoregulatory cytokines by developing into diverse populations of effector and memory cells. The relative strength of phosphoinositide 3-kinase (PI3K) signaling early in the T cell response can dramatically influence downstream effector and memory T cell differentiation. We show that initial PI3K signaling during T cell activation results in up-regulation of the signaling scaffold B cell adaptor for PI3K (BCAP), which further potentiates PI3K signaling and promotes the accumulation of CD8+ T cells with a terminally differentiated effector phenotype. Accordingly, BCAP-deficient CD8+ T cells have attenuated clonal expansion and altered effector and memory T cell development following infection with Listeria monocytogenes. Thus, induction of BCAP serves as a positive feedback circuit to enhance PI3K signaling in activated CD8+ T cells, thereby acting as a molecular checkpoint regulating effector and memory T cell development.

scholarly journals Normal T-Cell Development and Immune Functions in TRIM-Deficient Mice

2006 ◽  
Vol 26 (9) ◽  
pp. 3639-3648 ◽  
Author(s):  
Uwe Kölsch ◽  
Börge Arndt ◽  
Dirk Reinhold ◽  
Jonathan A. Lindquist ◽  
Nicole Jüling ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Subsets ◽  
Immune Functions ◽  
Deficient Mice

ABSTRACT The transmembrane adaptor molecule TRIM is strongly expressed within thymus and in peripheral CD4+ T cells. Previous studies suggested that TRIM is an integral component of the T-cell receptor (TCR)/CD3 complex and might be involved in regulating TCR cycling. To elucidate the in vivo function of TRIM, we generated TRIM-deficient mice by homologous recombination. TRIM−/− mice develop normally and are healthy and fertile. However, the animals show a mild reduction in body weight that appears to be due to a decrease in the size and/or cellularity of many organs. The morphology and anatomy of nonlymphoid as well as primary and secondary lymphoid organs is normal. The frequency of thymocyte and peripheral T-cell subsets does not differ from control littermates. In addition, a detailed analysis of lymphocyte development revealed that TRIM is not required for either positive or negative selection. Although TRIM−/− CD4+ T cells showed an augmented phosphorylation of the serine/threonine kinase Akt, the in vitro characterization of peripheral T cells indicated that proliferation, survival, activation-induced cell death, migration, adhesion, TCR internalization and recycling, TCR-mediated calcium fluxes, tyrosine phosphorylation, and mitogen-activated protein family kinase activation are not affected in the absence of TRIM. Similarly, the in vivo immune response to T-dependent and T-independent antigens as well as the clinical course of experimental autoimmune encephalomyelitis, a complex Th1-mediated autoimmune model, is comparable to that of wild-type animals. Collectively, these results demonstrate that TRIM is dispensable for T-cell development and peripheral immune functions. The lack of an evident phenotype could indicate that TRIM shares redundant functions with other transmembrane adaptors involved in regulating the immune response.

Effects of LMO2 on Human T-Cell Development Are Modulated by Notch Signaling

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2470-2470
Author(s):  
James A Kennedy ◽  
Renata Teixeira ◽  
Sara Berthiaume ◽  
Frederic Barabe
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Notch Signaling ◽  
T Cell Differentiation ◽  
Human T Cell ◽  
T Cell Leukemogenesis

Abstract Abstract 2470 LMO2 is overexpressed in a significant percentage of human T cell acute lymphoblastic leukemia (T-ALL) and its locus has been the target of insertional mutagenesis in gene therapy trials. In the past years, 4 X-linked severe combined immunodeficiency (X-linked SCID) and one Wiskott-Aldrich syndrome (WAS) patients who were treated by retrovirus-mediated gene therapy developed T-ALL as a result of retroviral integration in the LMO2 locus. In these patients, leukemia developed 2 to 3 years after gene therapy without prior significant haematological abnormalities. However, both the latency of disease and the finding of additional somatic mutations and/or translocations in these leukemias suggest that the overexpression of LMO2 alone is insufficient to generate leukemia, a notion that has been supported by studies in mouse. Though LMO2 is typically recognized as a T-cell oncogene, reports have shown that it is also aberrantly expressed in acute myeloid leukemias (AML), chronic myeloid leukemia (CML), B-ALL and some non-hodgkin B cell lymphomas. In order to study the impact of LMO2 overexpression on human hematopoietic stem/progenitor cells, a lentiviral vector was used to express this oncogene together with EGFP in lineage-depleted umbilical cord blood. In myeloid-promoting cultures, LMO2 had no effect on either differentiation or proliferation. Moreover, the expression of LMO2 did not modify the frequency or lineage distribution of colony forming progenitors compared to controls. However, significant differences were noted when transduced cells were assayed on OP9-Delta-Like 1 (DL1) stroma, an in vitro system that promotes T cell proliferation and differentiation. Cells overexpressing LMO2 were blocked at the double negative stage (CD4-CD8-) of differentiation and proliferated 50 to 100 times more than control cells. However, these cells were not immortalized as they proliferated for a median of 75 days, versus 50 days for controls. Immunodeficient mice transplanted with primitive human hematopoietic cells expressing LMO2 (hereafter referred as LMO2 mice) had bone marrow engraftment levels comparable to controls at 20–24 weeks post-transplant. Neither B-lymphoid nor myeloid development were affected by LMO2 overexpression. Strikingly, in the thymus, the percentage of EGFP+ cells was significantly increased in LMO2 mice compared to controls (mean of 47.7% versus 8.8%, p=0.0001), clearly indicating that expression of this oncogene enhances thymic T-cell engraftment. We next analyzed the phenotype of LMO2-expressing T cells in the thymus and peripheral blood of these mice. Surprisingly, unlike our in vitro studies, there was no evidence of a block at the DN-stage of differentiation. Instead, there were significantly less EGFP+ DN cells in the thymi of LMO2 mice compared to controls (mean of 7.5% vs 14.5%, p=0.035). These results clearly demonstrate that unlike what was observed in OP9-DL1 co-cultures, LMO2 overexpression does not induce a block in T-cell differentiation in our in vivo system. One possible explanation for this difference is the constitutive NOTCH signaling provided via DL1 on stroma compared to the in vivo setting where LMO2-expressing cells would encounter different levels and forms of NOTCH signaling throughout development. To test this hypothesis, LMO2 cells were cultured on OP9-DL1 stroma for 50 days then switched onto OP9 stroma lacking NOTCH ligand. Upon transfer, the DN cells promptly stopped proliferating and differentiated into DP (CD4+CD8+) cells expressing CD3 and TCRαβ. Thus, our results suggest that in the in vivo setting, as cells migrate through the thymus and face a decrease in NOTCH signaling, LMO2 overexpression alone can promote proliferation, but is not sufficient to maintain a differentiation block. However, constitutive NOTCH signaling can cooperate with LMO2 overexpression to block T cell differentiation at a proliferative DN stage. Thus, one can postulate that LMO2 exerts a proliferative effect on developing T-cells in thymic regions with high levels of NOTCH signaling, potentially providing a setting for the development of secondary leukemogenic events. NOTCH mutations are common in human T-ALL and can therefore allow for LMO2 overexpressing cells to become independent of the stromal niche. Taken together, our results suggest cooperation between LMO2 overexpression and NOTCH signaling in human T-cell leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia

2020 ◽  
Vol 4 (12) ◽  
pp. 2611-2616 ◽  
Author(s):  
Marita Bosticardo ◽  
Francesca Pala ◽  
Enrica Calzoni ◽  
Ottavia M. Delmonte ◽  
Kerry Dobbs ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Cd8 Cells ◽  
Cd34 Cells ◽  
T Cell Lymphopenia ◽  
Stromal Cell Line

Abstract The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34+ cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. We observed a similar defect in a patient carrying a null IL2RG mutation. In contrast, CD34+ cells from a patient carrying a missense IL2RG mutation reached full T-cell maturation, although cell numbers were significantly lower than in controls. CD34+ cells from patients carrying RAG mutations were able to differentiate to CD4+CD8+ cells, but not to CD3+TCRαβ+ cells. Finally, normal T-cell differentiation was observed in a patient with complete DiGeorge syndrome, consistent with the extra-hematopoietic nature of the defect. The ATO system may help determine whether T-cell deficiency reflects hematopoietic or thymic intrinsic abnormalities and define the exact stage at which T-cell differentiation is blocked.

scholarly journals The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells

2019 ◽  
Author(s):  
Eliza Mari Kwesi-Maliepaard ◽  
Muhammad Assad Aslam ◽  
Mir Farshid Alemdehy ◽  
Teun van den Brand ◽  
Chelsea McLean ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Histone Methyltransferase ◽  
T Cell Differentiation ◽  
Cytotoxic T Cell

AbstractCytotoxic T-cell differentiation is guided by epigenome adaptations but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+ T cells. T-cell specific ablation of Dot1L resulted in loss of naïve CD8+ T cells and premature differentiation towards a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Without DOT1L, the memory-like CD8+ cells fail to acquire full effector functions in vitro and in vivo. Mechanistically, DOT1L controlled T-cell differentiation and function by ensuring normal T-cell receptor density and signaling, and by maintaining epigenetic identity, in part by indirectly supporting the repression of developmentally-regulated genes. Through our study DOT1L is emerging as a central player in physiology of CD8+ T cells, acting as a barrier to prevent premature differentiation and supporting the licensing of the full effector potential of cytotoxic T cells.

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