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Eosinophils et al. in Asthma
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Killer Lipid
Leukotriene B4 (LTB4), a bioactive lipid released from activated polymorphonuclear leukocytes (PMNs), was shown by Flamand and collaborators to trigger the in vitro release of 
-defensins from human PMNs. In a continuation of that work, Flamand et al. (p. 8046
) determined that infectivity of HSV-1, two variants of HIV-1, Escherichia coli, and Staphylococcus aureus, was reduced >90% by incubation with the supernatant of human PMNs stimulated ex vivo with LTB4; most LTB4 structural analogs were inactive. Release of antimicrobial compounds from PMNs occurred within 1 min of exposure to LTB4. PMN supernatants contained a high concentration of -defensin and at least five other proteins identified by mass spectrometry. Plasma levels of -defensin increased in macaques within 2 h of receiving LTB4 by i.v. bolus.
The animals experienced transient neutropenia within 2 min of injection, followed by neutrophilia that reached a maximum at 30 min until 2 h. Highest antimicrobial activity was measured in plasma samples taken 2–4 h after injection. Radiolabeled LTB4 given i.v. was rapidly cleared from the circulation within 2 min of injection. The authors show that LTB4 induces rapid release of antimicrobial molecules, including -defensin, from human PMNs in vitro and increases PMN and plasma -defensin levels in monkeys.
Treg Cells Require STAT6
There are indications that STAT6 influences CD4+ Th2 T cell proliferation. However, it is not known if STAT6 plays a role in the development of CD4+CD25+FoxP3+ regulatory T (Treg) cells. Sanchez-Guajardo et al. (p. 7557 ) adoptively transferred T cell-depleted bone marrow cells from wild-type, STAT4–/–, or STAT6–/– mice, all transgenic for an influenza virus hemagglutinin-specific TCR (TCR-HA), into lethally irradiated Rag2–/– mice. Some of the recipients were transgenic for Ig promoter-driven expression of HA (IgHA). Among recipients of wild-type TCR-HA cells, HA-specific CD4+ single-positive (SP) thymocytes were reduced in the HA-expressing thymus compared with the HA-free thymus, whereas SP cells were slightly reduced in HA-expressing and HA-free thymi of donors given STAT4–/– or STAT6–/– TCR-HA cells. Peripheral CD4+ T cell numbers were equivalent in all three HA-free bone marrow chimeras but reduced in TCR-HA chimeras. Treg generation in the absence of HA was low in the three groups but preferentially reduced in TCR-HA chimeras reconstituted with STAT6–/– bone marrow. The few SP T cells recovered from HA-expressing chimeras reconstituted with STAT4–/– plus STAT6–/– TCR-HA cells of different Thy1 allotypes reflected the injected cell ratios, but the fraction of Treg cells was higher for STAT4–/– vs STAT6–/– TCR-HA cells. IL-4 treatment of Treg cells induced phosphorylated STAT6, and transgenic mice constitutively expressing STAT6 had higher numbers of peripheral Treg cells than controls. The data suggest that Treg generation in the thymus and FoxP3 expression in thymocytes requires both agonist-driven TCR and STAT6-mediated signals.
Regulating Granule Exocytosis
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and/or 
isoforms. CTLs from mice deficient in PKC , but not those deficient in PKC , had reduced cytolytic activity in chromium release assays compared with wild-type CTLs. PKC –/– CTLs formed conjugates with target cells in vitro. Activated mutant cells stimulated with plate-bound anti-CD3 Ab did not release 
-hexosaminidase or granzyme A or translocate lysosome-associated membrane protein-1; however, they had intracellular levels of granzyme B and perforin similar to those of wild-type cells. Defective cytolysis was reversed by nucleofection of a vector expressing the PKC gene into PKC –/– CTLs. Confocal microscopy using intracellular stains specific for -tubulin and granzyme B demonstrated the inability of PKC –/– CTLs to polarize microtubule organizing centers and lytic granules, respectively, toward the target cell contact site. The authors identify PKC as a positive regulator and inducer of lytic granule exocytosis in CTLs. Short Telomeres in Old T Cells
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, respectively, after in vitro stimulation with anti-CD3 Ab plus APCs; CD28–CD27– cells produced perforin. Levels of telomerase activity were highest in activated CD28+ T cells. Proliferation and telomerase activity were induced in stimulated CD8+ T cells transfected with chimeric molecules containing signaling regions from several other costimulatory molecules. However, transfection of CD28–CD27– cells with a CD28 chimeric signaling molecule did not restore stimulation-induced proliferation or telomerase induction. Addition of IL-2 or IL-15 reversed their low in vitro survival rate and proliferation compared with CD28+CD27+ and CD28–CD27+ cells; telomerase up-regulation was partially restored. An Akt kinase inhibitor decreased telomerase activity in all three CD8+ T cell subsets; the decrease correlated with lack of serine 473 phosphorylation in untreated CD28–CD27– cells and with its reduction in CD28–CD27+ cells. The authors conclude that the decrease in memory T cells with aging results from loss of telomerase up-regulation due to a defect in Akt phosphorylation. Faster Is Better Than More
Immunoproteasome subunits replace constitutive catalytic proteasome subunits in microbial infected tissues and professional APCs, resulting in rapid generation and presentation of MHC class I epitopes. However, it is not clear whether peptide amounts or speed of processing controls immunodominance. Deol et al. (p. 7563 ) inserted two adenovirus epitopes into Listeria monocytogenes (rLM-E1). Early 1B peptide (E1B192–200) is processed predominantly by immunoproteasomes, whereas E1A234–243 is processed in the absence or presence of immunoproteasomes. CD8+ T splenocytes from infected C57BL/6 (B6) mice had vigorous in vitro responses to E1B192–200 compared with E1A234–243. Primary and recall infection with rLM-E1 bacteria in B6 mice deficient for immunoproteasome subunits low molecular mass polypeptide 7 (LMP7) and multicatalytic endopeptidase complex-like-1 (MECL-1) resulted in in vitro CD8+ T cell responses to E1A234–243, but not to E1B192–200, peptide. Splenocytes from LMP7–/– MECL-1–/– mice given GM-CSF-expanded wild-type bone marrow-derived dendritic cells pulsed with E1B192–200 responded to rLM-E1 infection in vivo and to E1B192–200 peptide in vitro. Inhibitor analyses of MHC class I cell surface transport showed similar slow kinetics for E1A234–243 peptide in infected LMP7–/– MECL-1–/– and B6 mice but rapid kinetics for E1B192–200 peptide only in B6 controls. Splenocytes from LMP7–/– MECL-1–/– mice depleted of CD4+ and CD8+ T cells before rLM-E1 infection were transferred to uninfected LMP7–/– MECL-1–/– mice. Splenocytes from recipient animals exhibited vigorous in vitro responses to both peptides. The data suggest that rapid processing of some epitopes by immunoproteasomes favors an early CD8+ T response to them.
Coevolution of IgA and FcRI
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RI. However, bacteria decoy proteins, such as staphylococcal superantigen-like protein 7 (SSL7) of Staphylococcus aureus, bind with IgA to block its interaction with FcRI. To examine the influence of this competition on the evolution of the FCAR gene and of IgA, Abi-Rached et al. (p. 7955
) sequenced cDNAs of human and chimpanzee donors and found extensive species-specific FCAR polymorphism. Pairwise comparison of synonymous and nonsynonymous substitution rates indicated positive selection for the receptor domain that contacts IgA. Site and branch analyses identified nine positions for positive selection, seven of which clustered into two regions containing most of the IgA binding sites and other sites known to affect IgA binding. Some of these changes correlated with positively selected changes in the IgA C2 domain that could influence binding to FcRI. Evidence for positive selection of IgA mutations that reduced SSL7 binding was found in analyses of primate and rodent IgAs. These studies indicate that mutations that increase IgA binding to its receptor rather than to SSL7 confer a host advantage, whereas mutations in SSL7 that increase its binding to IgA confer pathogen advantage. The authors present a two-stage model that incorporates their findings on pathogen-driven evolution of IgA-FcRIinteractions. Summaries written by Dorothy L. Buchhagen, Ph.D.
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