The Journal of Immunology, 2004, 173: 3-4.
Copyright © 2004 by The American Association of Immunologists
IN THIS ISSUE
Limited perforin expression in rectal mucosal CD8+ T cells
Human immunodeficiency virus-1 can infect humans via the mucosa. Since HIV-1-specific CD8+ T cells from blood kill via a perforin-dependent mechanism, CD8+ T cells in GALT should limit retroviral infection. However, the effector functions of human intestinal T cells in situ had not been established. Schacklett et al. (p. 641
) used MHC class I tetramers specific for a gag epitope to demonstrate HIV-1-specific CD8+ T cells in rectal mucosa from HIV-1-positive individuals. Granzyme A protein was abundant and perforin protein levels were high in CD8+ T cells from blood of both healthy and virus-infected individuals. However, granzyme protein was abundant but perforin protein levels were very low in rectal CD8+ T cells from both groups. A similar pattern of expression was seen by immunohistochemical staining of rectal tissue from virus-infected patients and controls. Perforin mRNA was detected at a higher level in rectal T cells from HIV-1-positive individuals compared with healthy controls although the levels in both groups were considerably lower than detected in PBMC from either group. HIV-1-specific CD8+ T cells from blood and rectal tissue produced equivalent levels of IFN-
in response to HIV-1 peptide stimulation. CD8+ T cells in rectal tissue from HIV-1-positive individuals were equal in maturation state to those from blood but both populations were less mature than those from rectal tissue of healthy individuals. The authors speculate that the low levels of perforin in CD8+ T cells and the lower number of effector cells in intestinal tissue might enable HIV-1 and other sexually transmitted pathogens to gain entry more easily.
Evolution of the classical complement pathway
The mammalian complement system consists of three activation pathways: lectin, alternative, and classical. The classical pathway is thought to have evolved as a series of gene duplication events before its first appearance in jawed fish. Boshra et al. (p. 349
) molecularly cloned the 
-chain of C4 from liver RNA of rainbow trout and found that it was similar to the C4B isotype in higher vertebrates. The investigators also purified trout C4 molecules, comprised of -, 
-, and -chains, from trout plasma. C4 molecules bound two to three times more strongly to sensitized SRBC than to nonsensitized SRBC; the binding was Ca2+ dependent. Addition of purified trout C4 and C3 molecules restored classical pathway-dependent hemolytic activity against SRBC to trout serum depleted of C3 and C4. The highest levels of hemolysis occurred in the presence of Ca2+ or Mg2+. C1s prepared from trout plasma cleaved >90% of the trout C4 -chain at the site predicted from its amino acid sequence but was unable to cleave purified trout C3 molecules; divalent cations were not required for C4 -chain cleavage. Alternative pathway components Bf/C2 and Df, purified from trout plasma, cleaved trout C3 but failed to cleave trout C4. The data show that activation of the classical pathway is similar in teleosts and mammalian vertebrates and that the components of the alternative or classical pathways function only within one pathway.
Adenosine receptor regulates inflammation
Inflammatory damage to endothelial cells initiates a process that prevents damage to normal tissues. Although the A2A adenosine receptor (A2AR) is known to be involved in the process, its mechanism of action was not understood. Lukashev et al. (p. 21
) compared the expression of proinflammatory cytokine mRNAs in mice treated with agents that activated Toll-like receptors. LPS-induced septic shock resulted in more rapid death of A2AR-deficient mice than of wild-type mice. Intraperitoneal injection of CpG DNA or LPS led to high serum levels of IL-12p40 and TNF- in A2AR-deficient mice, but not in wild-type controls, and were accompanied by high transcription levels of those and other proinflammatory cytokines in splenocytes. Wild-type animals demonstrated a similar transcriptional up-regulation when pretreated with an A2AR antagonist before CpG DNA injection; pretreatment with an A2AR agonist prevented the up-regulation. Stronger NF-
B DNA binding and faster degradation of IB molecules were seen in extracts of peritoneal macrophages from CpG DNA-injected A2AR-deficient mice compared with wild-type controls. The authors suggest that their results support a model of physiologic negative feedback regulation of inflammation whereby extracellular adenosine interacts with A2AR to terminate the inflammatory response.
Defining diabetes resistance genes
Diabetes protection has been mapped to the Idd5 region on mouse chromosome 1 using congenic strains of nonobese diabetic (NOD) mice carrying the diabetes-resistant locus of the C57BL/10 (B10) or C56BL/6 (B6) mouse. However, the identity of the gene(s) responsible for type 1 diabetes (T1D) within the two mapped Idd5 loci was unknown. Wicker et al. (p. 164
) constructed a set of congenic mouse strains to define the proximal and distal boundaries of the two loci, Idd5.1 and Idd5.2, and established their sizes as 2.1 Mb and 1.52 Mb, respectively. The Idd5.1 region contained four genes, two of which, Ctla4 and Icos (inducible costimulator), encode proteins important in immune function. Two exonic single nucleotide polymorphisms (SNPs), one each in Ctla4 and Icos, were detected in a comparison of gene sequences from NOD and B6 mice. Steady-state levels of mRNAs in B10 Idd5.1 T cells were higher for the "ligand-independent" form of CTLA-4 (liCTLA-4), resulting from the SNP in exon 2, compared with NOD T cells. Levels of mRNA for three isoforms (full-length, li, and soluble) of CTLA-4 were higher in memory vs naive CD4+ T cells from both strains. In vivo, SRBC challenge of SRBC-primed mice resulted in higher expression of liCTLA-4 mRNA only in footpads from Idd5.1/Idd5.2 congenic mice compared with NOD mice. No differences in expression of ICOS mRNAs were seen in unstimulated or activated T cells from either strain. The Idd5.2 region contained 45 genes. A companion paper by Greve et al. (p. 157
) detected higher levels of ICOS expression on unstimulated CD4+ T cells from B10 Idd5.1 mice than from NOD mice, but the converse was found on activated T cells. CTLA-4 expression was higher on activated T cells from the congenic animals. NOD Idd5.1 mice developed more severe experimental autoimmune encephalomyelitis than NOD mice, but isolated NOD CD4+ T cells produced higher amounts of IL-10 after stimulation than cells from NOD Idd5.1 mice. Wicker et al. interpret their results as indicating that Idd5.1, the diabetes susceptibility gene, is Ctla4, whereas Greve et al. conclude that differences in ICOS expression are genetically controlled by the Idd5.1 locus and result in partial inhibition of diabetes but enhancement of experimental autoimmune encephalomyelitis in Idd5.1 mice. In partial resolution of their different conclusions, Greve et al. suggest that the lower ICOS expression in NOD Idd5.1 congenic mice results from high expression of liCTLA-4.
Thymic involution
To explain the thymic involution that occurs with increasing age, current models point to an inability of thymic stromal cells and hormones to support a constant level of T cell production. Research by Min et al. (p. 245
) challenged those models by focusing on the most immature bone marrow-derived T cell precursor, the early T-lineage progenitor (ETP). Whereas the triple-negative populations of intrathymic T cell progenitors decreased in numbers in old mice compared with young mice, their frequencies did not change significantly with age. However, ETPs declined in both frequency and absolute cell number with age. ETPs from young mice expanded into CD4+ T and CD8+ T cell populations when seeded into fetal thymic lobes; ETPs from old mice generated far fewer T cells. This reduced ETP proliferative capacity with age paralleled a decrease in expression of a nuclear Ag found in dividing cells and an increase in apoptosis as determined by annexin V labeling. The findings support a revised model whereby thymic involution occurs by age-related developmental defects in the earliest intrathymic progenitors.
Synthetic defensins prevent HIV-1 infection
Defensins are antimicrobial peptides that are comprised of three subfamilies designated , , and 
. Whereas -defensins from mammals have anti-HIV-1 activity, a comparable activity of -defensins, present as pseudogenes in the human genome, had not been determined. Wang et al. (p. 515
) synthesized two human -defensins, retrocyclin-1 and retrocyclin-2, containing either nine or one repeats, respectively, of a nonapeptide encoded within the DNA sequence of one pseudogene. Retrocyclin-1 was a lectin that bound to carbohydrate-containing proteins. Prior addition of retrocyclin-2 to a line of HeLa cell-derived indicator cells reduced the infectivity of primary isolates of HIV-1 and was approximately twice as potent as -defensin (HNP) isolated from human neutrophils; retrocyclin-1 was less effective. Rhesus monkey -defensins 1, 2, and 3 also decreased HIV-1 infection in vitro. HNPs 1–3 and retrocyclin-2 bound glycosylated HIV-1 gp120 and CD4 in surface plasmon resonance experiments, but no binding to deglycosylated gp120 was detected. Both fetal calf and human sera reduced binding of retrocyclins and HNPs to gp120. The authors propose that the administration of synthetic -defensins, the retrocyclins, could prevent viral infections at mucosal surfaces.
PGE2 suppression of phagocytosis
Prostaglandin E2, elevated in lungs during bacterial pneumonia, promotes inflammation while acting as a local immunosuppressant. However, its effect on alveolar macrophages (AMs) has not been investigated thoroughly. Aronoff et al. (p. 559
) found a suppression of FcR-mediated phagocytosis by rat AMs treated with PGE2 before incubation with IgG-opsonized SRBC or opsonized bacteria. The suppression was reversed by treatment of AMs with cyclooxygenase inhibitors. Intracellular cAMP production was stimulated in AMs treated with a highly selective agonist for EP2, a G-protein-coupled receptor for PGE2. Suppression of phagocytosis also was enhanced by treatment of AMs with a direct activator of adenylate cyclase; pretreatment of cells with a compound that blocked the degradation of cAMP further suppressed phagocytosis induced by the adenylate cyclase activator or PGE2. An EP2 receptor antagonist abrogated inhibition of phagocytosis by an EP2 agonist. Agonists for other EP receptors had no effect on phagocytosis. PGE2 inhibited phagocytosis of opsonized bacteria by AMs from wild-type, but not from EP2 knockout, mice. The data demonstrate that exogenous and endogenous PGE2 inhibit rat AM phagocytosis of bacteria by a cAMP-dependent mechanism mediated by the EP2 receptor.
Summaries written by Dorothy L. Buchhagen, Ph.D.
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