The Journal of Immunology, 2004, 172: 745-746.
Copyright © 2004 by The American Association of Immunologists
IN THIS ISSUE
IgE in parasite immunity
Both humans and mice react to infection with parasitic helminths by producing large amounts of IgE in addition to hyperplasia of mast cells (MC) and eosinophils in the small intestine. Yet, it is not clear that IgE plays a direct role in immunity to primary parasite infection. Gurish et al. (p. 1139) studied responses of wild-type and IgE-deficient BALB/c mice to infection by the gastrointestinal nematode Trichinella spiralis. Both strains of mice had comparable numbers of eosinophils at 11 and 21–28 days postinfection (p.i.) and MC at 14 days p.i. in the small intestine. However, the IgE-/- mice had reduced numbers of MC in their spleens and lower serum levels of mast cell protease-1 compared with wild-type mice through 28 days p.i. Worm burden was consistently higher in the infected IgE-deficient mice beginning at day 7 p.i.; and at 28 days p.i., the number of tongue cysts was double and the number of necrotic cysts was approximately one-third of those seen in infected wild-type mice. IgE serum levels in infected wild-type mice increased dramatically to 14 days p.i., and immunostaining showed significant binding of IgE to T. spiralis encysted larvae in infected wild-type animals. The authors propose that IgE controls T. spiralis infection by facilitating expulsion of worms from the intestine and of larvae from muscle, as well as by activating intestinal MC and by regulating splenic MC.
Polymorphic IL-4R
and asthma
Cytokines produced by Th2 lymphocytes infiltrating the lung are responsible for many features of asthma. There are conflicting observations regarding the susceptibility of IL-13-/- mice to allergic lung disease. Webb et al. (p. 1092) crossed IL-13-/- mice of 129 x C57BL/6 background to BALB/c mice for either 5 (N5) or 10 (N10) generations. OVA-sensitized N5 IL-13-/- mice developed airway hyperreactivity, robust tissue eosinophilia, elevated levels of Ag-specific IgE, and increased expression of Ym proteins (responsible for vascular smooth muscle differentiation and tissue remodeling) compared with N5 IL-13-/- mice treated with anti-IL-4 Ab and with OVA-sensitized N10 IL-13-/- mice. Purified N10 IL-13-/- OVA-sensitized spleen cells were induced to differentiate to Th2 in vitro by incubation with OVA, anti-IFN-
, and IL-4. These induced Th2 cells produced 46% less IL-4 and IL-5 than similarly treated N5 IL-13-/- Th2 cells. DNA sequence analyses revealed that the IL-4 receptor subunit (IL-4R) in the N5 IL-13-/- mice was of C57BL/6 origin, whereas that in N10 IL-13-/- mice was of BALB/c origin. The receptor subunits differed by nine amino acids, one of which reduced glycosylation at a critical extracellular IL-4 recognition site in the N10 IL-13-/- receptor subunit. The authors suggest that this polymorphism, which increases the dissociation rate of IL-4 and limits the intensity of signaling by IL-4R, interferes with the ability of IL-4 to substitute for IL-13 during allergic inflammation.
NK tumor immunity
The NKG2D receptor is found on NK and CD8+ T cells and plays a key role in antitumor immune responses. A TAP-deficient variant of T cell lymphoma-derived RMA cells (RMA-S) expressing the NKG2D ligand Rae1
(RMA-S-Rae1) is rejected in vivo by NK cell perforin-mediated cytotoxicity. Westwood et al. (p. 757) found that 57% of C57BL/6 (B6) mice that had rejected those tumors remained tumor free upon secondary challenge with RMA cells compared with 0% of naive B6 mice injected with RMA cells and 14% of primed B6 mice given a secondary challenge with RMA-S cells. No naive or primed mice given a syngeneic tumor survived. Depletion of both CD4+ and CD8+ T cells in the primed mice at the time of secondary challenge resulted in loss of the protective effect. Single depletion of either CD4+ or CD8+ T cells slightly reduced the numbers of tumor-free animals (50% and 38%, respectively) compared with 63% of controls. Depletion of either cell population at the time of priming did not affect rejection of primary RMA-S-Rae1 tumors. However, depletion of CD4+ T cells, but not CD8+ T cells, at the time of priming reduced the secondary response to RMA tumors. Neither IFN- nor IL-12 was required for either the primary or secondary response. The authors propose that NK cell NKG2D-triggered tumor immunity requires CD4+ T cell help. However, the help is independent of the conventional Th1 pathway.
Microflora and mucosal immunity
Intestinal microflora aid in the development of gut-associated lymphoid tissues (GALT) and in the generation of a diverse preimmune Ab repertoire in rabbits. Due to the complexity of host-bacteria interactions, the role that specific bacteria play in these responses has not been fully defined. Rhee et al. (p. 1118) introduced bacteria into the appendices of 4-wk-old rabbits rendered germfree by microsurgery (germfree-appendix rabbits). Ethanol-treated Bacteroides fragilis in combination with Bacillus subtilis or Staphylococcus epidermidis induced GALT development as measured by immunostaining with Abs against IgM and a nuclear protein present in proliferating cells. B. fragilis alone and B. fragilis and B. subtilis in combination, but rarely B. subtilis alone, were taken up by M cells, the specialized epithelial cells in domes within GALT that transport bacteria and particulate Ags to underlying immune cells. However, B. subtilis alone, but not B. fragilis, promoted GALT development. Two bacterial genes necessary for GALT development were identified by the introduction of stress-response mutant strains of B. subtilis into germfree appendices. Somatic diversification of Ig genes, as determined by VH gene nucleotide changes at seven weeks, occurred in response to cointroduction of B. fragilis and B. subtilis. The authors conclude that GALT development and somatic diversification in rabbits require two stress response genes in B. subtilis, and that B. fragilis enhances B. subtilis uptake by M cells.
Improving dendritic cell immunotherapy
Successful antitumor therapies based on dendritic cells (DC) pulsed with peptide Ags or genetically modified to present Ags depend on DC encountering T cells. Matsuyoshi et al. (p. 776) improved a method recently developed in their laboratory, to generate DC from embryonic stem (ES) cells. ES cells were transfected sequentially with vectors expressing an OVA peptide and one of three T cell-attracting chemokines not produced by DC. The double transfectants and mock infected OVA-expressing ES cells were differentiated to DC. DC coexpressing OVA and any of the chemokines had enhanced in vivo capacity, compared with DC expressing OVA alone, to prime OVA-specific CTL to kill, in vitro, mouse thymoma cells prepulsed with OVA peptide. Of the three chemokines transfected, coexpression of either secondary lymphoid tissue chemokine (SLC) or monokine induced by IFN- (Mig) was more effective than lymphotactin (Lptn) in priming CTL. Tumor size was smallest and survival time longest in mice injected twice i.p. with DC coexpressing OVA and SLC followed by challenge with OVA-expressing mouse melanoma cells. DC coexpressing OVA and Mig or Lptn provided protective immunity comparable to that seen with DC expressing OVA alone. Increasing the number of cells inoculated boosted the protective effect of DC coexpressing SLC or Mig above that seen with DC expressing OVA alone, but the protective immunity of DC coexpressing Lptn remained comparable to that of the DC expressing OVA alone. Protective immunity of DC expressing OVA alone or SLC and OVA was lost in mice treated with anti-CD4 or anti-CD8 mAb in vivo. The data demonstrate that ES cell-derived DC coexpressing SLC and a tumor peptide protect mice against peptide-expressing tumor cells by inducing antitumor- specific T cells.
MHC class I and II alleles in diabetes
Susceptibility and resistance to type 1 diabetes (T1D) in nonobese diabetic (NOD) mice is controlled by MHC class II alleles. Although pancreatic cell autoreactive CD8+ T cells can be deleted in the thymus or rendered anergic, the extent to which MHC class I variants participate has not been determined. Serreze et al. (p. 871) crossed NOD mice transgenically expressing the TCR from a diabetogenic Kd MHC class I-restricted effector CD8+ T cell clone (AI4Tg) with NOD mice carrying H2 MHC class II alleles that dominantly inhibit T1D (NOD.AI4 Tg mice). T1D incidence in (NOD.H2nbl x NOD.AI4 Tg)F1 female mice was reduced to 0% through 30 wk of age compared with a 90% incidence by 10 wk of age in NOD.AI4 Tg females carrying the diabetogenic MHC class II haplotype variant, H2-Ag7. Bone marrow chimeras of NOD mice reconstituted with F1 marrow cells had fewer AI4 CD8+ and CD4+/CD8+ T cells than control animals. Female (NOD x NOD.H2b)F1 hybrids reconstituted with a 1:1 mixture of syngeneic F1 and NOD.Rag1null.AI4 Tg bone marrow remained diabetes-free 6 wk postreconstitution. Diabetogenic NOD.Rag1null.AI4 Tg T cells were partially anergized after maturing in the presence of H2b or H2b-Ab0 APC, had decreased levels of TCR expression and did not induce T1D after infusion into NOD/SCID recipients. The results indicate that while the peripheral effector function of AI4 T cells was MHC class I restricted, the AI4 TCR could engage class II variants encoded by H2nbl during thymic maturation resulting in negative selection. In addition, AI4 T cells could be functionally anergized by down-regulation of TCR expression following interaction with H2b class I molecules.
TLR2 activation in synovial fibroblasts
Bacterial peptidoglycan (PGN) has been detected in the joints of patients with rheumatoid arthritis (RA). Although Toll-like receptors (TLR) bind PGN and are expressed on synovial fibroblasts of patients with RA, there is no evidence that any TLR is directly involved in autoimmune inflammatory reactions. Using high density microarray based analyses, Pierer et al. (p. 1256) detected the up-regulation of 74 genes in RA-synovial fibroblasts (SF) in response to TLR2 activation by PGN; 14 encoded chemokines. PGN and bacterial lipopeptide (BLP) strongly up-regulated expression of granulocyte chemotactic protein-2 (GCP-2), monocyte chemotactic protein-2 (MCP-2) and RANTES in RA-SF and, to a lesser extent, in osteoarthritic (OA)-SF. The chemokine induction was abolished by pretreatment of RA-SF cells with a 5 µM concentration of an inhibitor of I
B phosphorylation and of NF-B activation. Supernatants from PGN-treated RA-SF cultures had a nearly three-fold higher chemotactic effect on PBMC in Boyden chamber assays than supernatants from untreated RA-SF cultures. Blocking Abs against RANTES or MCP-2 or both, but not Abs against GCP-2, reduced migration of CD14+ monocytes. Concentrations of GCP-2 and MCP-2 were significantly higher in synovial fluids from RA patients compared with OA patients or patients diagnosed with other inflammatory arthritides. These two chemokines were found histochemically in CD68- fibroblasts in synovial tissues from RA, but not OA, patients. The authors propose that activation of TLR2 in synovial fibroblasts induces expression of GCP-2 and MCP-1 in RA.
Summaries written by Dorothy L. Buchhagen, Ph.D.
