RESUMO
Signal-transducing adaptor protein-2 (STAP-2) is a unique scaffold protein that regulates several immunological signaling pathways, including LIF/LIF receptor and LPS/TLR4 signals. STAP-2 is required for Fas/FasL-dependent T cell apoptosis and SDF-1α-induced T cell migration. Conversely, STAP-2 modulates integrin-mediated T cell adhesion, suggesting that STAP-2 is essential for several negative and positive T cell functions. However, whether STAP-2 is involved in T cell-antigen receptor (TCR)-mediated T cell activation is unknown. STAP-2 deficiency was recently reported to suppress TCR-mediated T cell activation by inhibiting LCK-mediated CD3ζ and ZAP-70 activation. Using STAP-2 deficient mice, it was demonstrated that STAP-2 is required for the pathogenesis of Propionibacterium acnes-induced granuloma formation and experimental autoimmune encephalomyelitis. Here, detailed functions of STAP-2 in TCR-mediated T cell activation, and how STAP-2 affects the pathogenesis of T cell-mediated inflammation and immune diseases, are reviewed.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Transdução de Sinais , Linfócitos T , Proteína-Tirosina Quinase ZAP-70 , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Complexo CD3 , Adesão Celular , Movimento Celular , Quimiocina CXCL12/fisiologia , Quimiocina CXCL12/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/etiologia , Inflamação/imunologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/fisiologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Propionibacterium acnes/fisiologia , Propionibacterium acnes/imunologia , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Proteína-Tirosina Quinase ZAP-70/metabolismo , Proteína-Tirosina Quinase ZAP-70/fisiologiaRESUMO
Signal-transducing adaptor protein (STAP)-1 is an adaptor protein that is widely expressed in T cells. In this article, we show that STAP-1 upregulates TCR-mediated T cell activation and T cell-mediated airway inflammation. Using STAP-1 knockout mice and STAP-1-overexpressing Jurkat cells, we found that STAP-1 enhanced TCR signaling, resulting in increased calcium mobilization, NFAT activity, and IL-2 production. Upon TCR engagement, STAP-1 binding to ITK promoted formation of ITK-LCK and ITK-phospholipase Cγ1 complexes to induce downstream signaling. Consistent with the results, STAP-1 deficiency reduced the severity of symptoms in experimental autoimmune encephalomyelitis. Single-cell RNA-sequencing analysis revealed that STAP-1 is essential for accumulation of T cells and Ifng and Il17 expression in spinal cords after experimental autoimmune encephalomyelitis induction. Th1 and Th17 development was also attenuated in STAP-1 knockout naive T cells. Taken together, STAP-1 enhances TCR signaling and plays a role in T cell-mediated immune disorders.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Encefalomielite Autoimune Experimental , Inflamação , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Inflamação/metabolismo , Inflamação/patologia , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Transdução de SinaisRESUMO
Although signal-transducing adaptor protein-2 (STAP-2) acts in certain immune responses, its role in B cell receptor (BCR)-mediated signals remains unknown. In this study, we have revealed that BCR-mediated signals, cytokine production and antibody production were increased in STAP-2 knockout (KO) mice compared with wild-type (WT) mice. Phosphorylation of tyrosine-protein kinase LYN Y508 was reduced in STAP-2 KO B cells after BCR stimulation. Mechanistic analysis revealed that STAP-2 directly binds to LYN, dependently of STAP-2 Y250 phosphorylation by LYN. Furthermore, phosphorylation of STAP-2 enhanced interactions between LYN and tyrosine-protein kinase CSK, resulting in enhanced CSK-mediated LYN Y508 phosphorylation. These results suggest that STAP-2 is crucial for controlling BCR-mediated signals and antibody production by enhanced CSK-mediated feedback regulation of LYN.
Assuntos
Transdução de Sinais , Quinases da Família src , Camundongos , Animais , Proteína Tirosina Quinase CSK/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Fosforilação , Linfócitos B/metabolismo , Camundongos KnockoutRESUMO
Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that contains pleckstrin and Src homology 2-like domains, as well as a proline-rich region in its C-terminal region. Our previous study demonstrated that STAP-2 positively regulates TCR signaling by associating with TCR-proximal CD3ζ ITAMs and the lymphocyte-specific protein tyrosine kinase. In this study, we identify the STAP-2 interacting regions of CD3ζ ITAMs and show that the STAP-2-derived synthetic peptide (iSP2) directly interacts with the ITAM sequence and blocks the interactions between STAP-2 and CD3ζ ITAMs. Cell-penetrating iSP2 was delivered into human and murine T cells. iSP2 suppressed cell proliferation and TCR-induced IL-2 production. Importantly, iSP2 treatment suppressed TCR-mediated activation of naive CD4+ T cells and decreased immune responses in CD4+ T cell-mediated experimental autoimmune encephalomyelitis. It is likely that iSP2 is a novel immunomodulatory tool that modulates STAP-2-mediated activation of TCR signaling and represses the progression of autoimmune diseases.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Transdução de Sinais , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade , Receptores de Antígenos de Linfócitos T/metabolismo , Fragmentos de Peptídeos/farmacologiaAssuntos
Própole , Humanos , Própole/farmacologia , Própole/uso terapêutico , Basófilos , Imunoglobulina ERESUMO
Signal-transducing adaptor family member-2 (STAP-2) is an adaptor protein that regulates various intracellular signals. We previously demonstrated that STAP-2 binds to epidermal growth factor receptor (EGFR) and facilitates its stability and activation of EGFR signaling in prostate cancer cells. Inhibition of this interaction may be a promising direction for cancer treatment. Here, we found that 2D5 peptide, a STAP-2-derived peptide, blocked STAP-2-EGFR interactions and suppressed EGFR-mediated proliferation in several cancer cell lines. 2D5 peptide inhibited tumor growth of human prostate cancer cell line DU145 and human lung cancer cell line A549 in murine xenograft models. Additionally, we determined that EGFR signaling and its stability were decreased by 2D5 peptide treatment during EGF stimulation. In conclusion, our study shows that 2D5 peptide is a novel anticancer peptide that inhibits STAP-2-mediated activation of EGFR signaling and suppresses prostate and lung cancer progression.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Pulmonares , Peptídeos , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Células A549 , Linhagem Celular Tumoral , Peptídeos/farmacologiaRESUMO
Adaptor molecules play a crucial role in signal transduction in immune cells. Several adaptor molecules, such as the linker for the activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76), are essential for T cell development and activation following T cell receptor (TCR) aggregation, suggesting that adaptor molecules are good therapeutic targets for T cell-mediated immune disorders, such as autoimmune diseases and allergies. Signal-transducing adaptor protein (STAP)-2 is a member of the STAP family of adaptor proteins. STAP-2 functions as a scaffold for various intracellular proteins, including BRK, signal transducer, and activator of transcription (STAT)3, STAT5, and myeloid differentiation primary response protein (MyD88). In T cells, STAP-2 is involved in stromal cell-derived factor (SDF)-1α-induced migration, integrin-dependent cell adhesion, and Fas-mediated apoptosis. We previously reported the critical function of STAP-2 in TCR-mediated T cell activation and T cell-mediated autoimmune diseases. Here, we review how STAP-2 affects the pathogenesis of T cell-mediated inflammation and immune diseases in order to develop novel STAP-2-targeting therapeutic strategies.
RESUMO
Damage-associated molecular patterns (DAMPs) contribute to antitumor immunity during cancer chemotherapy. We previously demonstrated that topotecan (TPT), a topoisomerase I inhibitor, induces DAMP secretion from cancer cells, which activates STING-mediated antitumor immune responses. However, how TPT induces DAMP secretion in cancer cells is yet to be elucidated. Here, we identified RPL15, a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited preribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. TPT inhibits RPL15-RPL4 interactions and decreases RPL4 stability, which is recovered by CDK12 activity. RPL15 knockdown induced DAMP secretion and increased the CTL population but decreased the regulatory T cell population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against PD-1 blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy.
Assuntos
Neoplasias , Topotecan , Animais , Camundongos , Neoplasias/tratamento farmacológico , Proteínas Ribossômicas , Inibidores da Topoisomerase I/farmacologia , Topotecan/farmacologia , Topotecan/uso terapêuticoRESUMO
TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, and proliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responses against a variety of pathogens. We here propose signal-transducing adaptor protein-2 (STAP-2) as a new positive regulator of TCR signaling. STAP-2-deficient T cells showed reduced, whereas STAP-2-overexpressing T cells showed enhanced, TCR-mediated signaling and downstream IL-2 production. For the mechanisms, STAP-2 associated with TCR-proximal CD3ζ immunoreceptor tyrosine activation motifs and phosphorylated LCK, resulting in enhancement of their binding after TCR stimulation. In parallel, STAP-2 expression is required for full activation of downstream TCR signaling. Importantly, STAP-2-deficient mice exhibited slight phenotypes of CD4+ T-cell-mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis, whereas STAP-2-overexpressing transgenic mice showed severe phenotypes of these diseases. Together, STAP-2 is an adaptor protein to enhance TCR signaling; therefore, manipulating STAP-2 will have an ability to improve the treatment of patients with autoimmune diseases as well as the chimeric Ag receptor T cell therapy.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transdução de Sinais , Animais , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos TRESUMO
Interleukin-17A (IL-17A) is a cytokine that affects the functions of non-immune cells, including keratinocytes, and thereby amplifies immune responses. An IκB family protein IκB-ζ, encoded by the NFKBIZ gene, mediates IL-17A-induced inflammatory cellular responses. Previously we reported that a transcription factor STAT3 mediates the transcriptional induction of NFKBIZ through its binding to the specific binding site existing in the NFKBIZ promoter. However, it remains unclear how other transcription factors regulate NFKBIZ transcription. Here, we investigated the NFKBIZ promoter regulation by transcription factors C/EBPß and STAT1 and revealed opposing roles of C/EBPß and STAT1 in NFKBIZ transcription. We found that siRNA-mediated knockdown of C/EBPß attenuates IL-17A-induced upregulation of NFKBIZ in the HaCaT cell line. A putative C/EBP-binding site is located adjacent to the STAT-binding site in the NFKBIZ promoter, the deletion of which abolished C/EBPß-driven promoter activation in transient NFKBIZ promoter-luciferase assay. Deleting the STAT-binding site also led to a reduction in C/EBPß-driven promoter activation, suggesting a cooperative action between C/EBP- and STAT-binding sites. Furthermore, Co-overexpression of STAT1 suppressed both C/EBPß- and STAT3-driven NFKBIZ promoter activation independently of its tyrosine 701 phosphorylation. siRNA-mediated STAT1 knockdown augmented IκB-ζ induction in IL-17A-treated HaCaT cells, with enhanced expression of an IκB-ζ target gene DEFB4A. Together, these results indicate that both C/EBPß and STAT3 are transcription factors that coordinately induce NFKBIZ promoter activation, indicating that STAT1 has an inhibitory role. Thus, these could be a fine-tuning mechanism of IL-17A-IκB-ζ-mediated cellular responses.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT , Interleucina-17 , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica , Interleucina-17/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Jak3, a member of the Janus kinase family, is essential for the cytokine receptor common gamma chain (γc)-mediated signaling. During activation of Jak3, tyrosine residues are phosphorylated and potentially regulate its kinase activity. We identified a novel tyrosine phosphorylation site within mouse Jak3, Y820, which is conserved in human Jak3, Y824. IL-2-induced tyrosine phosphorylation of Jak3 Y824 in human T cell line HuT78 cells was detected by using a phosphospecific, pY824, antibody. Mutation of mouse Jak3 Y820 to alanine (Y820A) showed increased autophosphorylation of Jak3 and enhanced signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation and transcriptional activation. Stably expressed Jak3 Y820A in F7 cells, an IL-2 responsive mouse pro-B cell line Ba/F3, exhibited enhanced IL-2-dependent cell growth. Mechanistic studies demonstrated that interaction between Jak3 and STAT5 increased in Jak3 Y820A compared to wild-type Jak3. These data suggest that Jak3 Y820 plays a role in negative regulation of Jak3-mediated STAT5 signaling cascade upon IL-2-stimulation. We speculate that this occurs through an interaction promoted by the tyrosine phosphorylated Y820 or a conformational change by Y820 mutation with either the STAT directly or with the recruitment of molecules such as phosphatases via a SH2 interaction. Additional studies will focus on these interactions as Jak3 plays a crucial role in disease and health.
Assuntos
Fator de Transcrição STAT5 , Tirosina , Animais , Interleucina-2/metabolismo , Interleucina-2/farmacologia , Janus Quinase 3 , Camundongos , Proteínas do Leite/metabolismo , Fosforilação , Fator de Transcrição STAT5/metabolismo , Transdução de SinaisRESUMO
Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein involved in inflammatory and immune responses, such as inflammatory bowel disease and allergic responses. In this study, we investigated the role of STAP-2 in the pathogenesis of autoimmune hepatitis. After intravenous injection of concanavalin A (ConA), STAP-2 knock out (KO) mice showed more severe liver necrosis along with substantial lymphocyte infiltration compared to wild type (WT) mice. Serum alanine aminotransferase levels were significantly higher in ConA-injected STAP-2 KO mice than in WT mice. Levels of interferon-γ (IFN-γ), an important factor for liver necrosis, were also significantly increased in sera of STAP-2 KO mice compared to WT mice after ConA injection. Statistically significant upregulation of Fas ligand (FasL) expression was observed in the livers of ConA-injected STAP-2 KO mice compared to WT mice. In accordance with these results, apoptotic signals were facilitated in STAP-2 KO mice compared to WT mice after ConA injection. Correctively, these results suggest that STAP-2 is involved in the pathogenesis of autoimmune hepatitis by regulating the expression of FasL and the production of IFN-γ.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Ligante Fas/metabolismo , Hepatite Autoimune/metabolismo , Interferon gama/metabolismo , Fígado/patologia , Animais , Apoptose , Caspase 3/metabolismo , Concanavalina A , Modelos Animais de Doenças , Feminino , Fígado/metabolismo , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Transdução de Sinais , Regulação para CimaRESUMO
Signal-transducing adaptor protein (STAP)-2 is one of the STAP family adaptor proteins and ubiquitously expressed in a variety types of cells. Although STAP-2 is required for modification of FcεRI signal transduction in mast cells, other involvement of STAP-2 in mast cell functions is unknown, yet. In the present study, we mainly investigated functional roles of STAP-2 in IL-33-induced mast cell activation. In STAP-2-deficient, but not STAP-1-deficient, mast cells, IL-33-induced IL-6 and TNF-α production was significantly decreased compared with that of wild-type mast cells. In addition, STAP-2-deficiency greatly reduced TLR4-mediated mast cell activation and cytokine production. For the mechanisms, STAP-2 directly binds to IKKα after IL-33 stimulation, leading to elevated NF-κB activity. In conclusion, STAP-2, but not STAP-1, participates in IL-33-induced mast cells activation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Interleucina-33/metabolismo , Mastócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Células Cultivadas , Citocinas/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Chronic myeloid leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia chromosome and its oncogenic product, BCR-ABL, which activates multiple pathways involved in cell survival, growth promotion, and disease progression. We recently reported that signal-transducing adaptor protein 1 (STAP-1) is upregulated in CML stem cells (LSCs) and functions to reduce the apoptosis of CML LSCs by upregulating the STAT5-downstream anti-apoptotic genes. In this study, we demonstrate the detailed molecular interactions among BCR-ABL, STAP-1, and signal transducer and activator of transcription 5 (STAT5). Studies with deletion mutants have revealed that STAP-1 interacts with BCR-ABL and STAT5a through its SH2 and PH domains, respectively, suggesting the possible role of STAP-1 as a scaffold protein. Furthermore, the binding of STAP-1 to BCR-ABL stabilizes the BCR-ABL protein in CML cells. Since STAP-1 is highly expressed in CML cells, we also analyzed the STAP-1 promoter activity using a luciferase reporter construct and found that NFATc1 is involved in activating the STAP-1 promoter and inducing STAP-1 mRNA expression. Our results demonstrate that STAP-1 contributes to the BCR-ABL/STAT5 and BCR-ABL/Ca2+/NFAT signals to induce proliferation and STAP-1 mRNA expression in CML cells, respectively.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição NFATC/metabolismo , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0241440.].
RESUMO
We previously reported that synovial mast cells (MCs) from patients with rheumatoid arthritis (RA) produced TNF-α in response to immune complexes via FcγRI and FcγRIIA. However, the specific functions of synovial MCs in RA remain unclear. This study aimed to elucidate those functions. Synovial tissues and fluid were obtained from RA and osteoarthritis (OA) patients undergoing joint replacement surgery. Synovium-derived, cultured MCs were generated by culturing dispersed synovial cells with stem cell factor. We performed microarray-based screening of mRNA and microRNA (miRNA), followed by quantitative RT-PCR-based verification. Synovial MCs from RA patients showed significantly higher prostaglandin systhetase (PTGS)1 and PTGS2 expression compared with OA patients' MCs, and they produced significantly more prostaglandin D2 (PGD2) following aggregation of FcγRI. PGD2 induced IL-8 production by human group 2 innate lymphoid cells, suggesting that PGD2-producing MCs induce neutrophil recruitment into the synovium of RA patients. PTGS2 mRNA expression in RA patients' MCs correlated inversely with miRNA-199a-3p expression, which down-regulated PTGS2. RA patients' synovial fluid contained significantly more PGD2 compared with OA patients' fluid. Synovial MCs might regulate inflammation in RA through hyper-production of PGD2 following FcRγ aggregation. Our findings indicate functional heterogeneity of human MCs among diseases.
Assuntos
Artrite Reumatoide/patologia , Ciclo-Oxigenase 2/metabolismo , Mastócitos/metabolismo , MicroRNAs/metabolismo , Osteoartrite/patologia , Prostaglandina D2/biossíntese , Transdução de Sinais , Membrana Sinovial/patologia , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/genética , Células Cultivadas , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Feminino , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Liberação de Histamina , Humanos , Imunidade Inata , Interleucina-8/biossíntese , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Osteoartrite/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de IgG/metabolismo , Líquido Sinovial/metabolismoRESUMO
CD47, a 50 kDa transmembrane protein, facilitates integrin-mediated cell adhesion and inhibits cell engulfment by phagocytes. Since CD47 blocking promotes engulfment of cancer cells by macrophages, it is important to clarify the mechanism of CD47 signaling in order to develop treatments for diseases involving CD47-overexpressing cancer cells, including breast cancer and lymphoma. Here, we show that CD47 plays an essential role in T-cell lymphoma metastasis by up-regulating basal RhoA activity independent of its anti-phagocytic function. CD47 interacts with AKAP13, a RhoA-specific guanine nucleotide exchange factor (GEF), and facilitates AKAP13-mediated RhoA activation. Our study shows that CD47 has a novel function on the AKAP13-RhoA axis and suggests that CD47-AKAP13 interaction would be a novel target for T-cell lymphoma treatment.
Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Antígeno CD47/metabolismo , Linfoma de Células T/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Metástase Neoplásica/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Linfoma de Células T/patologia , Macrófagos/metabolismo , Fagocitose , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologiaRESUMO
Graft-versus-host disease (GVHD) is the most frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is one of the major causes of non-relapse mortality. Transferred mature lymphocytes are thought to be responsible for GVHD based on the findings that mice transplanted with lymphocyte-depleted bone marrow (BM) cells from MHC-mismatched donors do not develop GVHD. However, we found that overexpression of signal-transducing adaptor protein (STAP)-2 in lymphoid cells could induce GVHD after lymphocyte-depleted BM transplantation. To examine the function of STAP-2, which has been shown to play an important role in development and function of lymphocytes, in GVHD, we transplanted BM cells from STAP-2 deficient, or Lck promoter/IgH enhancer-driven STAP-2 transgenic (Tg) mice into MHC-mismatched recipients. Unexpectedly, mice transplanted with lymphocyte-depleted BM cells from STAP-2 Tg mice developed severe acute GVHD with extensive colitis and atrophy of thymus, while no obvious GVHD developed in mice transplanted with the wild type or STAP-2 deficient graft. Furthermore, mice transplanted with lymphocyte-depleted BM cells from the syngeneic STAP-2 Tg mice developed modest GVHD with colitis and atrophy of thymus. These results suggest that STAP-2 overexpression may enhance survival of allo-, and even auto-, reactive lymphocytes derived from engrafted hematopoietic progenitor cells in lethally irradiated mice, and that clarification of the mechanism may help understanding induction of immune tolerance after HSCT.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células da Medula Óssea/imunologia , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/imunologia , Depleção Linfocítica , Doença Aguda , Animais , Contagem de Linfócitos , Complexo Principal de Histocompatibilidade , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Transplante HomólogoRESUMO
Signal-transducing adaptor protein-2 (STAP-2) was discovered as a C-FMS/M-CSFR interacting protein and subsequently found to function as an adaptor of signaling or transcription factors. These include STAT5, MyD88 and IκB kinase in macrophages, mast cells, and T cells. There is additional information about roles for STAP-2 in several types of malignant diseases including chronic myeloid leukemia, however, none have been reported concerning B lineage lymphocytes. We have now exploited gene targeted and transgenic mice to address this lack of knowledge, and demonstrated that STAP-2 is not required under normal, steady-state conditions. However, recovery of B cells following transplantation was augmented in the absence of STAP-2. This appeared to be restricted to cells of B cell lineage with myeloid rebound noted as unremarkable. Furthermore, all hematological parameters were observed to be normal once recovery from transplantation was complete. Furthermore, overexpression of STAP-2, specifically in lymphoid cells, resulted in reduced numbers of late-stage B cell progenitors within the bone marrow. While numbers of mature peripheral B and T cells were unaffected, recovery from sub-lethal irradiation or transplantation was dramatically reduced. Lipopolysaccharide (LPS) normally suppresses B precursor expansion in response to interleukin 7, however, STAP-2 deficiency made these cells more resistant. Preliminary RNA-Seq analyses indicated multiple signaling pathways in B progenitors as STAP-2-dependent. These findings suggest that STAP-2 modulates formation of B lymphocytes in demand conditions. Further study of this adapter protein could reveal ways to speed recovery of humoral immunity following chemotherapy or transplantation.