Premature Expression of Chemokine Receptor CCR9 Impairs T Cell Development

Uehara, Shotaro; Hayes, Sandra M.; Li, LiQi; El-Khoury, Dalal; Cañelles, Matilde; Fowlkes, B. J.; Love, Paul E.

doi:10.4049/jimmunol.176.1.75

Cited by 33 publications

(37 citation statements)

References 38 publications

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“…CC chemokine receptor-9 (CCR9) is a GPCR and plays an important role in T cell development and tissue-specific homing when binding to its specific ligand CCL25, which is also known as thymus-expressed chemokine (TECK) [7]. Chemokines are also important for solid tumor apoptosis.…”

Section: Introductionmentioning

confidence: 99%

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

Wang

Zhong

et al. 2015

Med Oncol

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CC chemokine receptor-9 (CCR9) is highly expressed in non-small cell lung cancer (NSCLC) tissues and cell lines. However, the biological functions and the signals elicited by the interaction between CCR9 and its natural ligand CCL25 in NSCLC are unknown. Here, we selectively depleted CCR9 and inhibited CCR9-CCL25 interaction in NSCLC cells using small recombinant lentivirus-mediated miRNA, and investigated the tumorigenic effects in vitro and in vivo. Compromised CCR9-CCL25 interaction promoted apoptosis in NSCLC cells by activating phosphoinositide 3-kinase (PI3K)/Akt in vitro. In addition, we showed that CCR9-CCL25 interaction mediated the activation of the PI3K/Akt pathway in NSCLC cells, resulting in the up-regulation of anti-apoptotic proteins, as well as the down-regulation of apoptotic proteins in a PI3K-/Akt-dependent manner. These CCR9-CCL25-mediated effects were abrogated in the presence of a PI3K inhibitor (wortmannin 10 nM) or by inhibiting the CCR9-CCL25 interaction through CCR9 silencing, which also suggested that the biological function of CCR9-CCL25 was mainly regulated by PI3K. In vivo studies also demonstrated a significantly lower tumor burden in mice receiving CCR9-silence cells than those in mice receiving control cells. Together, these data suggested that CCR9-CCL25 interaction induced tumorigenesis of NSCLC cells and that this induction might be accomplished through the activation of the PI3K/Akt pathway. These findings may lead to a better understanding of the biological effects of CCR9-CCL25 interaction and provide clues for identifying novel therapeutic and preventive molecular markers for NSCLC.

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Section: Introductionmentioning

confidence: 99%

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

Wang

Zhong

et al. 2015

Med Oncol

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“…Phenotypically, SP thymocytes are traditionally sub-divided into “semi-mature” CD24 hi Qa2 lo , and “mature” CD24 lo Qa2 hi populations. The expression of chemokine receptors, CCR9, CCR7 and CCR4 changes during SP thymocyte maturation to ensure their transit from the cortex to medulla (3–6). Thymic maturation also involves upregulation of IL-7Rα, which is required for T cell survival and homeostasis in the periphery (7).…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase 3 Is Required for T Cell Maturation

Hsu

Belmonte

Constans

et al. 2015

The Journal of Immunology

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Recent thymic emigrants (RTEs) are newly generated T cells that need to undergo post-thymic maturation to gain functional competency and enter the long-lived naïve T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. As NKAP associates with histone deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. While thymic populations are similar in CD4-cre HDAC3 conditional knockout (cKO) mice compared to wild-type (WT) mice, however, the peripheral numbers of CD4+ and CD8+ T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naïve T cells are RTEs, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 cKO mice do not have a defect in intrathymic migration, thymic egress, T cell survival or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation.

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“…The migration of thymocytes through these distinct microenvironments is important for proper T cell development, as shown by the developmental arrest that results from preventing DN migration towards the capsule (Misslitz et al, 2004; Plotkin et al, 2003; Uehara et al, 2006), or the autoimmunity that ensues when SP cells are blocked from entering the medulla (Kurobe et al, 2006; Ueno et al, 2004). The mechanisms contributing to thymocyte localization are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Differential Contribution of Chemotaxis and Substrate Restriction to Segregation of Immature and Mature Thymocytes

et al. 2009

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SUMMARY T cell development requires sequential localization of thymocyte subsets to distinct thymic microenvironments. To address mechanisms governing this segregation, we used 2-photon microscopy to visualize the migration of purified thymocyte subsets in defined microenvironments within thymic slices. Double-negative (CD4−8−) and double-positive (CD4+8+; DP) thymocytes were strictly confined to cortex where they moved slowly without directional bias. DP cells accumulated and migrated more rapidly in a specialized inner-cortical microenvironment, but were excluded from the medulla by an inability to migrate on medullary substrates. In contrast, CD4 single-positive (SP) thymocytes migrated directionally towards the medulla, where they accumulated and moved very rapidly. Our results reveal a requisite two-step process governing CD4 SP medullary localization: the chemokine receptor CCR7 mediated chemotaxis of CD4 SP cells towards the medulla, whereas a distinct pertussis-toxin sensitive pathway was required for medullary entry. These findings suggest that developmentally regulated responses to both chemotactic signals and specific migratory substrates guide thymocytes to specific locations in the thymus as they mature.

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Premature Expression of Chemokine Receptor CCR9 Impairs T Cell Development

Cited by 33 publications

References 38 publications

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

Histone Deacetylase 3 Is Required for T Cell Maturation

Differential Contribution of Chemotaxis and Substrate Restriction to Segregation of Immature and Mature Thymocytes

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