Luciana L Molinero

Publications (25) View all

• Article: T cell receptor/CARMA1/NF-κB signaling controls T-helper (Th) 17 differentiation.

  Luciana L Molinero, Alan Cubre, Carolina Mora-Solano, Ying Wang, Maria-Luisa Alegre
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  ABSTRACT: IL-17-producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor κB (NF-κB) is required for T-cell activation and selected effector functions, but its role in Th17 differentiation is controversial. Using genetic mouse models that impede T-cell-NF-κB signaling either downstream of the T-cell receptor (TCR) or of IκB kinase β (IKKβ), we demonstrate that NF-κB signaling controls not only survival and proliferation of activated T cells, but, if cell survival and cell-cycle progression are enabled, has an additional role in promoting completion of Th17 differentiation. CARD-containing MAGUK protein 1 (CARMA1), an adapter required for TCR/NF-κB signaling, was necessary for acquisition of IL-17A, IL-17F, IL-21, IL-22, IL-23R, and CCR6 expression in T cells cultured under Th17 conditions. In proliferating cells, lack of CARMA1 selectively prevented Th17, but not Th1 or Th2 differentiation, in a cell-intrinsic manner. Consistent with these data, CARMA1-KO mice were resistant to experimental autoimmune encephalomyelitis. Surprisingly, transcription factors essential for Th17 differentiation such as RORγt, AHR, and IRF4 were normally induced in CARMA1-KO T cells activated under Th17 conditions, suggesting that the Th17 differentiation program was initiated normally. Instead, chromatin loci of Th17 effector molecules failed to acquire an open conformation in CARMA1-KO T cells. Our results demonstrate that TCR/CARMA1/NF-κB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci.
  Proceedings of the National Academy of Sciences 10/2012; · 9.68 Impact Factor
• Article: The inside story of dendritic cell immunotherapy.

  M-L Alegre, L L Molinero
  American Journal of Transplantation 06/2012; 12(6):1363-4. · 6.39 Impact Factor
• Article: Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome.

  Sangeeta M Bhorade, Hong Chen, Luciana Molinero, Chuanhong Liao, Edward R Garrity, Wickii T Vigneswaran, Rebecca Shilling, Anne Sperling, Anita Chong, Maria-Luisa Alegre
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  ABSTRACT: Lung transplantation, in patients with end-stage lung disease, is limited by chronic rejection, which occurs with an incidence and severity exceeding most other transplanted organs. Alloimmune responses play an important role in progression to chronic rejection that manifests as bronchiolitis obliterans syndrome (BOS), but no biomarker can currently predict the progression to BOS. Studies in animal models suggest that intragraft T regulatory cells (Tregs) are important in maintaining transplantation tolerance, and FoxP3 is the protoypic Treg marker. Leukocytes in blood and bronchoalveolar lavage (BAL) fluid were compared for expression of FoxP3 by flow cytometry in 14 stable lung transplant recipients and 6 lung transplant recipients who eventually developed BOS. Stable patients, compared with patients who subsequently developed BOS, consistently had a significantly increased percentage of FoxP3 cells among CD4 cells in BAL and greater levels of the Treg-attracting chemokine CCL22. These differences were observed in limited sequential analyses, before, at the time of acute rejection, and postacute rejection. In this pilot study, a threshold of 3.2% CD4/FoxP3 cells in the BAL distinguished stable recipients from those subsequently developing BOS within the first 2 years posttransplantation. The proportion of FoxP3 cells among CD4 cells in BAL may help to predict lung allograft outcome and guide therapeutic immunosuppression in lung transplant recipients.
  Transplantation 09/2010; 90(5):540-6. · 4.00 Impact Factor
• Article: Fas mediates cardiac allograft acceptance in mice with impaired T-cell-intrinsic NF-kappaB signaling.

  Luciana Lorena Molinero, Ying Wang, Ping Zhou, Hideo Yagita, Maria-Luisa Alegre
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  ABSTRACT: The transcription factor NF-kappaB is critical for T-cell activation and survival. We have shown that mice expressing a T-cell-restricted NF-kappaB superrepressor (IkappaBalphaDeltaN-Tg) permanently accept heart but not skin allografts. Overexpression of the prosurvival factor Bcl-x(L) in T cells restored heart rejection, suggesting that graft acceptance in IkappaBalphaDeltaN-Tg mice was attributable to deletion of alloreactive T cells.In vitro, the increased death of IkappaBalphaDeltaN-Tg T cells upon TCR stimulation when compared with wildtype T cells was mostly because of Fas/FasL interaction. Similarly, Fas played a key role in cardiac allograft acceptance by IkappaBalphaDeltaN-Tg mice as both genetic and antibody-mediated inhibition of Fas-signaling restored cardiac allograft rejection. Rejection correlated with graft infiltration by T cells and splenic production of IFN-gamma upon allostimulation. These results indicate that T-cell inhibition of NF-kappaB results in cardiac allograft acceptance because of increased susceptibility to Fas-mediated cell death.
  Transplant International 05/2009; 22(8):845-52. · 2.92 Impact Factor
• Article: CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells.

  Luciana L Molinero, Jianying Yang, Thomas Gajewski, Clara Abraham, Michael A Farrar, Maria-Luisa Alegre
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  ABSTRACT: Natural regulatory T cells (nTregs) that develop in the thymus are essential to limit immune responses and prevent autoimmunity. However, the steps necessary for their thymic development are incompletely understood. The CARMA1/Bcl10/Malt1 (CBM) complex, comprised of adaptors that link the TCR to the transcription factor NF-kappaB, is required for development of regulatory T cells (Tregs) but not conventional T cells. Current models propose that TCR-NF-kappaB is needed in a Treg-extrinsic manner for IL-2 production by conventional T cells or in already precommitted Treg precursors for driving IL-2/STAT5 responsiveness and further maturation into Tregs and/or for promoting cell survival. Using CARMA1-knockout mice, our data show instead that the CBM complex is needed in a Treg-intrinsic rather than -extrinsic manner. Constitutive activity of STAT5 or protection from apoptosis by transgenic expression of Bcl2 in developing Tregs is not sufficient to rescue CARMA1-knockout Treg development. Instead, our results demonstrate that the CBM complex controls an early checkpoint in Treg development by enabling generation of thymic precursors of Tregs. These data suggest a modified model of nTreg development in which TCR-CBM-dependent signals are essential to commit immature thymocytes to the nTreg lineage.
  The Journal of Immunology 07/2009; 182(11):6736-43. · 5.79 Impact Factor