RESUMO
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy is the strongest predictor of relapse, suggesting that strategies to eliminate the residual leukemic blasts from this niche could reduce the incidence of recurrence. We have previously reported that toll-like receptor (TLR) agonists achieve durable T cell-mediated protection in transplantable cell line-based models of B cell precursor leukemia (B-ALL). However, the successful application of TLR agonist therapy in an MRD setting would require the induction of anti-leukemic immune activity specifically in the bone marrow, a site of the chemotherapy-resistant leukemic blasts. In this study, we compare the organ-specific depletion of human and mouse primary B-ALL cells after systemic administration of endosomal TLR agonists. Despite comparable splenic responses, only the TLR9 agonist induced strong innate immune responses in the bone marrow and achieved a near-complete elimination of B-ALL cells. This pattern of response was associated with the most significantly prolonged disease-free survival. Overall, our findings identify innate immune activity in the bone marrow that is associated with durable TLR-induced protection against B-ALL outgrowth.
RESUMO
Individuals with X-linked lymphoproliferative disease lack invariant natural killer T (iNKT) cells and are exquisitely susceptible to Epstein-Barr virus (EBV) infection. To determine whether iNKT cells recognize or regulate EBV, resting B cells were infected with EBV in the presence or absence of iNKT cells. The depletion of iNKT cells increased both viral titers and the frequency of EBV-infected B cells. However, EBV-infected B cells rapidly lost expression of the iNKT cell receptor ligand CD1d, abrogating iNKT cell recognition. To determine whether induced CD1d expression could restore iNKT recognition in EBV-infected cells, lymphoblastoid cell lines (LCL) were treated with AM580, a synthetic retinoic acid receptor-α agonist that upregulates CD1d expression via the nuclear protein, lymphoid enhancer-binding factor 1 (LEF-1). AM580 significantly reduced LEF-1 association at the CD1d promoter region, induced CD1d expression on LCL, and restored iNKT recognition of LCL. CD1d-expressing LCL elicited interferon γ secretion and cytotoxicity by iNKT cells even in the absence of exogenous antigen, suggesting an endogenous iNKT antigen is expressed during EBV infection. These data indicate that iNKT cells may be important for early, innate control of B cell infection by EBV and that downregulation of CD1d may allow EBV to circumvent iNKT cell-mediated immune recognition.
Assuntos
Linfócitos B/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Transtornos Linfoproliferativos/imunologia , Células T Matadoras Naturais/imunologia , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Linfócitos B/virologia , Comunicação Celular/imunologia , Transformação Celular Neoplásica/imunologia , Infecções por Vírus Epstein-Barr/complicações , Humanos , Imunidade Inata/imunologia , Fator 1 de Ligação ao Facilitador Linfoide/imunologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Transtornos Linfoproliferativos/virologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/virologia , Tonsila Palatina/imunologia , Tonsila Palatina/virologiaRESUMO
CD1d-restricted natural killer T (NKT) cells are emerging as critical regulators of the immune response to infectious agents, including Pseudomonas aeruginosa; and therapies to augment NKT-cell activation may represent a novel approach to treat chronic, antibiotic-resistant bacterial infections. We examined the capacity of dendritic cells (DCs) from people with cystic fibrosis (CF) to activate NKT cells. Our study was motivated by three lines of evidence: (i) NKT cells play a critical role in clearing P. aeruginosa infection; (ii) activation of NKT cells requires acidification-dependent processing of glycolipid antigens within the endolysosomal compartment; and (iii) endolysosomal acidification may be reduced in CF. We demonstrated that NKT-cell activation was dependent upon intact organelle acidification as inhibitors of the vacuolar (H(+))-ATPases prevented DCs from activating NKT cells with two glycolipid antigens, alpha-galactosylceramide and galactose-galactosylceramide. In contrast, cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel dysfunction had no significant biological impact on the capacity of DCs to activate NKT cells. Dendritic cells from subjects with CF and DCs treated with the thiazolidinone CFTR(inh)-172 inhibitor showed no reduction in their ability to activate NKT cells. Based on these data, we find no evidence for an inherent defect in glycolipid antigen presentation to NKT cells in CF subjects.
Assuntos
Antígenos CD1d/imunologia , Fibrose Cística/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/imunologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/imunologia , Endossomos/genética , Endossomos/imunologia , Endossomos/metabolismo , Endossomos/microbiologia , Feminino , Galactosilceramidas/genética , Galactosilceramidas/imunologia , Galactosilceramidas/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Masculino , Células T Matadoras Naturais/metabolismo , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Tiazolidinedionas/farmacologiaRESUMO
The CD1 antigen presentation system presents lipid antigens to effector T cells, which have diverse roles in antimicrobial responses, antitumor immunity and in regulating the balance between tolerance and autoimmunity. The trafficking of CD1 molecules and lipid antigens facilitates their intersection and binding in specific intracellular compartments. Recent studies have now identified unexpected accessory molecules that are critical to CD1 assembly and lipid loading. The atomic structures of CD1-antigen complexes have defined both the orientation of polar headgroups between the alpha1 and alpha2 helices of CD1 and the manner in which distinct CD1 isoforms bind a range of lipids that have different lengths and numbers of hydrocarbon chains.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos CD1/imunologia , Lipídeos/imunologia , Animais , Antígenos/química , Antígenos/imunologia , Antígenos CD1/química , Humanos , Lipídeos/química , Isoformas de Proteínas/química , Isoformas de Proteínas/imunologia , Estrutura Terciária de Proteína , Linfócitos T/imunologiaRESUMO
We studied T-bet expression in 91 cases of peripheral T-cell lymphoma (PTCL) by immunostaining and found expression in 42 cases (46%), including all 5 lymphoepithelioid lymphoma cases and 12 (86%) of 14 angioimmunoblastic lymphoma cases, but only 9 (25%) of 36 anaplastic large cell lymphoma cases. Expression of T-bet in PTCL correlates with expression of other markers of Th1 T-cell differentiation, including CXCR3 (P < .0001), CD69 (P = .0013), LEF-1 (P = .0007), and OX40/CD134 (P = .005), and absence of expression of markers of Th2 T-cell differentiation, including CD30 (P = .0001) and CXCR4 (P = .0144). Of 22 cases of PTCL immunoreactive for all Th1-associated markers previously studied and nonreactive for Th2-associated markers, 20 (91%) were immunoreactive for T-bet. Of 22 PTCL cases immunoreactive for Th2-associated markers studied and nonreactive for all Th1-associated markers studied, 4 (18%) were immunoreactive for T-bet. The remaining 47 PTCL cases (52%) exhibited incomplete or mixed staining for Th1- and Th2-associated markers, with 18 (38%) of 47 immunoreactive for T-bet. T-bet is a new marker that may contribute to the diagnosis and subtyping of PTCLs. T-bet expression in these neoplasms provides further support for a model of PTCL in which tumor subsets express markers of, and may be derived from, Th1- or Th2-committed T cells.