33 documents found, page 1 of 4
Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers...
Sumaria, Nital; Fiala, Gina; Inácio, Daniel; Curado Avelar, Marta Maria; Cachucho, Ana; Pinheiro, Rúben; Wiesheu, Robert; Kimura, ShunsukeThe contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αβ heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αβ+ γδ T cell development is directed by low T cell receptor signaling and through provision of interleukin (IL)-4 and IL-7. Th...
INPP5K controls the dynamic structure and signaling of wild-type and mutated, l...
Moës, Bastien; Li, Hua; Molina-Ortiz, Patricia; Radermecker, Coraline; Rosu, Adeline; Vande Catsyne, Charles-Andrew; Sayyed, Sufyan Ali; Fontela, JoãoThe downstream signaling of the interleukin-7 (IL-7) receptor (IL-7R) plays important physiological and pathological roles, including the differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain-of-function mutations in the IL-7Rα chain, the specific component of the receptor for IL-7, result in constitutive, IL-7-independent signaling and trigger acute lymphoblastic leuke...
An instructive role for Interleukin-7 receptor α in the development of human B-...
Geron, Ifat; Savino, Angela Maria; Fishman, Hila; Tal, Noa; Brown, John; Turati, Virginia A.; James, Chela; Sarno, Jolanda; Hameiri-Grossman, MichalKinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis "ph-like" BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and p...
Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia
Oliveira, Mariana L.; Veloso, Alexandra; Garcia, Elaine G.; Iyer, Sowmya; Pereira, Clara; Barreto, Vasco M.; Langenau, David M.; Barata, João T.T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric cancer. Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor α chain (IL-7Rα, encoded by IL7R), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, ...
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T ce...
Rocha, Sara; Basto, Afonso; Ijsselsteijn, Marieke E.; Teles, Sara P.; Azevedo, Maria M.; Gonçalves, Gilza; Gullo, Irene; Almeida, Gabriela M.Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophe...
Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia...
Silva, Ana; Almeida, Afonso; Cachucho, Ana; Neto, João Luís; Demeyer, Sofie; Ramos De Matos, Mafalda; Hogan, Thea; Li, Yunlei; Meijerink, JulesTight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains uncl...
Interleukin-7 receptor α mutational activation can initiate precursor B-cell ac...
Almeida, Afonso; Neto, João Luís; Cachucho, Ana; Euzébio, Mayara; Meng, Xiangyu; Kim, Rathana; Fernandes, Marta; Raposo, Beatriz; Oliveira, Mariana L.Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal a...
Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferati...
Perera, Yasser; Melão, Alice; Ramón, Ailyn C.; Vázquez, Dania; Ribeiro, Daniel; Perea, Silvio E.; Barata, João T.Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivatio...
IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: an update
Oliveira, Mariana L.; Akkapeddi, Padma; Ribeiro, Daniel; Melão, Alice; Barata, João T.Interleukin 7 (IL-7) and its receptor (IL-7R, a heterodimer of IL-7Rα and γc) are essential for normal lymphoid development. In their absence, severe combined immunodeficiency occurs. By contrast, excessive IL-7/IL-7R-mediated signaling can drive lymphoid leukemia development, disease acceleration and resistance to chemotherapy. IL-7 and IL-7R activate three main pathways: STAT5, PI3K/Akt/mTOR and MEK/Erk, ulti...
Flip the coin: IL-7 and IL-7R in health and disease
Barata, João T.; Durum, Scott K.; Seddon, BenedictThe cytokine IL-7 and its receptor, IL-7R, are critical for T cell and, in the mouse, B cell development, as well as differentiation and survival of naive T cells, and generation and maintenance of memory T cells. They are also required for innate lymphoid cell (ILC) development and maintenance, and consequently for generation of lymphoid structures and barrier defense. Here we discuss the central role of IL-7 ...