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Macrophage Clearance of Adenovirus
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5, important in adenovirus-mediated endosome lysis, were decreased at the protein and mRNA levels only in PU.1-expressing cells. Expression of PU.1 from a retrovirus vector reduced adenovirus transduction in A549 cells compared with untransfected controls, redirected virions from the nuclear membrane to paranuclear aggregates, and reduced integrin 5 mRNA and protein levels. The conclusion from the data is that GM-CSF blocks endosomal escape of adenovirus and prevents host infection via transcription factor PU.1 reduction of integrin 5. CD8+ T Cell Peripheral Tolerance
Peripheral self-reactive CD8+ T cells that escape thymic deletion face two fates: tolerance induction by Ag-presenting resting dendritic cells (DCs) or activation to cytotoxicity by DCs licensed by CD4+ T cells. It is not known whether licensed DCs interfere with tolerance induction. Steptoe et al. (p. 2094
) found that adoptively transferred CFSE-labeled T cells transgenic for an OVA-specific CD8+ (OT-I) or CD4+ (OT-II) TCR had greater proliferation in spleens of 11c.OVA mice expressing an OVA transgene under control of the CD11c promoter than wild-type controls. Proliferation was further increased with coadministration of anti-CD40 mAb. Cotransfer of the OT-1 and OT-II cells resulted in early expansion and late contraction of each population along with increased IFN-
and IL-2 production by OT-I T cells in vivo and by OVA peptide-stimulated OT-II T cells in vitro; anti-CD154 mAb prevented expansion of OT-I T cells. By 21 days posttransfer, residual OT-I or OT-II T cells were unable to produce IFN- in response to OVA peptide in vitro or to OVA/CFA immunization in vivo and had lost activation marker expression. CFSE-labeled OVA peptide-pulsed target cells injected into 11c.OVA mice 21 days posttransfer with OT-I and OT-II T cells were not killed unless the animals also were given anti-CD40 mAb. Cotransfer of OT-I and OT-II T cells into 11c.OVA mice also expressing OVA in pancreatic cells protected the animals against the diabetes that developed in controls after immunization with OVA/CFA. The experiments demonstrate that autoreactive CD4+ T cells do not impair peripheral autoreactive CD8+ T cell tolerance induction by resting DCs expressing the self-Ag.
New Way to Induce EAE Tolerance
Several laboratories have shown that Ag-pulsed, ethylene carbodiimide (ECDI)-fixed splenic APCs (Ag-SP) effectively anergize Ag-specific CD4+ T cells in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. However, the mechanism of tolerance induction by whole protein-ECDI-coupled splenocytes is not known. Turley and Miller (p. 2212 ) induced tolerance in wild-type mice injected i.v. with murine proteolipid protein (PLP) peptide-ECDI-fixed SP cells that were allogeneic, syngeneic, MHC class I deficient, or MHC class I plus class II deficient. Syngeneic or allogeneic PLP peptide-SP reduced EAE in SJL mice given activated Ag-specific CD4+ T cells or specific peptide. Tolerized mice had attenuated PLP Ag-specific delayed-type hypersensitivity reactions in response to Ag challenge compared with controls. Peptide-ECDI-fixed Ag-SP from mice expressing MHC class II molecules covalently linked with the same peptide induced attenuated peptide-specific responses. Fixation of SJL splenocytes with ECDI induced apoptosis as measured by high levels of intracellular caspase activity, up-regulated annexin V expression, and DNA fragmentation. Bone marrow-derived dendritic cells took up dye-labeled ECDI-Ag-SP after coincubation at 37°C. The experiments demonstrate an indirect mechanism of tolerance induction in EAE that uses host APC presentation of reprocessed allogeneic donor ECDI-Ag-SPs.
Hierarchy of Human CD3 Chains
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TCR heterodimers with invariant dimers CD3
, CD3, and 
(collectively referred to as CD3). Regueiro and colleagues reported that complete CD3 deficiency has a severe consequence in mice but has effects that range from mild to lethal in humans. In a continuation of their investigations, Recio et al. (p. 2556
) determined that two Turkish patients with CD3 deficiency had an exon 3 mutation in the CD3G gene identical to that reported in another Turkish family by a different laboratory. Haplotype analysis of microsatellite markers indicated that both families acquired the defective allele from a common founder. However, the two new patients developed clinical symptoms of SCID during infancy, whereas the teenage patient from the second family remains healthy. Of two Spanish brothers carrying a different CD3G gene mutation that the Regueiro group had described previously, one died early of SCID whereas the other is now 30 years old. All tested patients had very few peripheral blood thymus emigrants but had normal memory T cell pools and TCR V usage compared with age-matched controls. The authors propose that the disparate clinical manifestations of human CD3 deficiency reflect the influence of other genetic factors on the >>
hierarchy for impact of the missing chain on TCR/CD3 structure and on >> for signaling. Thymus Settling Is Selective
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p21 Control of T Cell Homeostasis
Balomenos and collaborators reported increased lupus in hybrid mice of mixed background deficient for the cell cycle inhibitor p21. Conflicting results from other laboratories prompted Arias et al. (p. 2296 ) in the Balomenos laboratory to examine the effects of p21 deficiency on a C57BL/6 (B6) background. No difference in apoptosis, as measured by several methods, was found between naive CD4+ T cells from wild-type or p21–/– B6 mice subjected to Con A stimulation followed by expansion in the presence of IL-2. However, the surviving p21-deficient cells had greater proliferation in response to subsequent Con A stimulation with or without IL-2 expansion compared with wild-type controls; surface markers indicated a memory CD4+ T cell phenotype. Protein levels of p21 on immunoblots increased in wild-type cells after primary stimulation and increased further after secondary stimulation. Accumulation of memory CD4+ T cells in spleens of p21–/– B6 mice was greater in females than in males. By 12 mo of age, p21–/– B6 mice had glomerular IgG deposits and developed levels of anti-dsDNA Ab that were higher than wild-type but lower than p21–/– mixed background control mice; female mice developed glomerulonephritis that was less severe than the p21–/– mixed background control mice. Memory CD4+ T cells from spleens of OVA-immunized p21–/–, but not wild-type, mice proliferated in response to stimulation in vitro with OVA plus irradiated splenocytes. The authors confirm that p21 regulates proliferation only of memory T cells that survive apoptosis induction and that its lack leads to lupus glomerulonephritis in aging B6 mice.
TLRs in Influenza Virus Infection
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) compared with wild-type controls. In contrast, significant elevation of IgG1 titers in serum and bronchoalveolar lavage fluid was detected in infected mice lacking TLR7 or MyD88; IgG2a/c titers were reduced only in the MyD88–/– animals. No differences in Ab isotypes were detected in infected mice lacking TLR4, TLR3, or TLR9. B cells incubated in vitro with a TLR7 ligand plus anti-CD40, but not with either reagent alone, underwent class switching to IgG2a/c that was enhanced by addition of IFN-. Both IgG1 and IgG2a/c levels were reduced in infected mice lacking CD40 or its ligand. Injected anti-CD40L Ab decreased virus-specific IgG2a/c Abs in infected wild-type and MyD88–/– mice. Higher IgG1 and lower IgG2a/c levels were measured in mice lacking the IFNR in infections with a high dose of influenza virus, whereas isotype levels were less perturbed in low dose virus infections. The authors conclude that TLR signaling, CD40/CD40L interactions, and type 1 IFN production control IgG isotype switching in influenza virus-infected B cells but that TLR signaling does not regulate antiviral T cell responses. Summaries written by Dorothy L. Buchhagen, Ph.D.
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