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1.
J Immunol ; 185(9): 5279-88, 2010 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-20921523

RESUMEN

Heme oxygenase-1 (HO-1) and its catabolic by-products have potent anti-inflammatory activity in many models of disease. It is not known, however, if HO-1 also plays a role in the homeostatic control of T cell activation and proliferation. We demonstrate here that the HO-1 inhibitor tin mesoporphyrin (SnMP) induces activation, proliferation, and maturation of naive CD4(+) and CD8(+) T cells via interactions with CD14(+) monocytes in vitro. This response is dependent upon interactions of T cells with MHC class I and II on the surface of CD14(+) monocytes. Furthermore, CD4(+)CD25(+)FoxP3(+) regulatory T cells were able to suppress this proliferation, even though their suppressive activity was itself impaired by SnMP. Given the magnitude of the Ag-independent T cell response induced by SnMP, we speculate that HO-1 plays an important role in dampening nonspecific T cell activation. Based on these findings, we propose a potential role for HO-1 in the control of naive T cell homeostatic proliferation.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Hemo-Oxigenasa 1/antagonistas & inhibidores , Activación de Linfocitos/efectos de los fármacos , Metaloporfirinas/farmacología , Linfocitos T/efectos de los fármacos , Western Blotting , Proliferación Celular/efectos de los fármacos , Separación Celular , Citometría de Flujo , Hemo-Oxigenasa 1/inmunología , Humanos , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/metabolismo , Activación de Linfocitos/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Linfocitos T/enzimología , Linfocitos T/inmunología
2.
Proc Natl Acad Sci U S A ; 105(25): 8718-23, 2008 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-18562290

RESUMEN

Originally recognized for their role in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) have also been implicated to play a key role in several biological processes not directly related to their lipid transport function. For example, apoE4 contributes significantly to neurodegeneration in Alzheimer's disease. However, the role of apoE in infectious diseases is less well defined. Here, by examining a large cohort of HIV(+) European and African American subjects, we found that the APOE epsilon4/epsilon4 genotype is associated with an accelerated disease course and especially progression to death compared with the APOE epsilon3/epsilon3 genotype. However, an association between the epsilon4/epsilon4 genotype and HIV-associated dementia (HAD), a neurological condition with clinicopathological features similar to Alzheimer's disease, was not detected. Consistent with the genotype-phenotype relationships observed, compared with recombinant apoE3, apoE4 enhanced HIV fusion/cell entry of both R5 and X4 HIV strains in vitro. These findings establish apoE as a determinant of HIV-AIDS pathogenesis and raise the possibility that current efforts to convert apoE4 to an "apoE3-like" molecule to treat Alzheimer's disease might also have clinical applicability in HIV disease.


Asunto(s)
Apolipoproteína E4/genética , Infecciones por VIH/genética , VIH-1/metabolismo , Alelos , Estudios de Cohortes , Genotipo , Infecciones por VIH/epidemiología , Humanos , Polimorfismo Genético , Factores de Riesgo , Células Tumorales Cultivadas
3.
Nat Commun ; 10(1): 3841, 2019 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-31451696

RESUMEN

Human lung tissue-resident NK cells (trNK cells) are likely to play an important role in host responses towards viral infections, inflammatory conditions and cancer. However, detailed insights into these cells are still largely lacking. Here we show, using RNA sequencing and flow cytometry-based analyses, that subsets of human lung CD69+CD16- NK cells display hallmarks of tissue-residency, including high expression of CD49a, CD103, and ZNF683, and reduced expression of SELL, S1PR5, and KLF2/3. CD49a+CD16- NK cells are functionally competent, and produce IFN-γ, TNF, MIP-1ß, and GM-CSF. After stimulation with IL-15, they upregulate perforin, granzyme B, and Ki67 to a similar degree as CD49a-CD16- NK cells. Comparing datasets from trNK cells in human lung and bone marrow with tissue-resident memory CD8+ T cells identifies core genes co-regulated either by tissue-residency, cell-type or location. Together, our data indicate that human lung trNK cells have distinct features, likely regulating their function in barrier immunity.


Asunto(s)
Inmunidad Mucosa , Células Asesinas Naturales/metabolismo , Enfermedades Pulmonares/inmunología , Pulmón/citología , Transcriptoma/inmunología , Anciano , Anciano de 80 o más Años , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Conjuntos de Datos como Asunto , Femenino , Humanos , Células Asesinas Naturales/inmunología , Pulmón/inmunología , Pulmón/cirugía , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Neumonectomía , RNA-Seq , Mucosa Respiratoria/citología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo
4.
J Immunol ; 172(11): 6626-33, 2004 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-15153477

RESUMEN

Costimulation through the CD40-CD40 ligand (CD40L) pathway is critical to allograft rejection, in that anti-CD40L mAb therapy prolongs allograft survival. However, the majority of studies exploring CD40-CD40L interactions have targeted CD40L. Less is known about the requirement for donor- and/or host-derived CD40 during rejection. This study assessed the relative contributions of donor and recipient CD40 expression to the rejection process. As the effectiveness of costimulatory blockade may be mouse strain dependent, this study explored the requirement for donor and recipient CD40 expression in BALB/c and C57BL/6 mice. Wild-type (WT) and CD40(-/-) BALB/c recipients readily rejected WT and CD40(-/-) C57BL/6 allografts, and rejection was associated with a prominent Th1 response. In contrast, CD40(-/-) C57BL/6 recipients failed to reject WT or CD40(-/-) BALB/c allografts and did not mount Th1 or Th2 responses. However, injection of donor CD40(-/-) dendritic cells induced both Th1 and Th2 responses and allograft rejection in CD40(-/-) C57BL/6 recipients. Finally, WT C57BL/6 mice rejected CD40(-/-) allografts, but this rejection response was associated with muted Th1 responses. These findings demonstrate that 1) CD40 expression by the recipient or the graft may impact on the immune response following transplantation; 2) the requirement for CD40 is influenced by the mouse strain; and 3) the requirement for CD40 in rejection may be bypassed by donor DC. Further, as CD40 is not required for rejection in BALB/c recipients, but anti-CD40L mAb prolongs graft survival in these mice, these results suggest that anti-CD40L therapy functions at a level beyond disruption of CD40-CD40L interactions.


Asunto(s)
Antígenos CD40/fisiología , Células Dendríticas/fisiología , Rechazo de Injerto/etiología , Trasplante de Corazón/inmunología , Células TH1/inmunología , Animales , Ligando de CD40/fisiología , Femenino , Interferón gamma/biosíntesis , Ratones , Ratones Endogámicos , Trasplante Homólogo
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