Regulating T cell anergy
In their role as APCs, dendritic cells are involved in the initiation and regulation of the T cell response to Ag. The T cell response is regulated not only by signaling through the TCR itself, but also by costimulatory or inhibitory accessory signals. Selenko-Gebaurer et al. (p. 3637 ) determined that the recently identified molecule B7-H1 functions as a dendritic cell inhibitory receptor. By generating and screening for mAbs capable of modulating the T cell response to dendritic cells, they determined that treatment of dendritic cells with either intact Ig or Fab fragments of mAb DF272 led to increased T cell proliferation, increased production of IFN-γ and IL-2 and decreased IL-10 production. Dendritic cells treated with mAb DF272 were also able to overcome the anergy induced in T cells by exposure to IL-10-treated dendritic cells. The authors then showed that mAb DF272 binds to B7-H1, a recently identified member of the B7 family of costimulatory molecules. B7-H1 expression on dendritic cells therefore appears to be involved in the induction and maintenance of T cell anergy, shedding new light on the role played by dendritic cells in T cell regulation.
Drug receptors
Sigma receptors, originally described as being expressed in the CNS, are also expressed in cells of the immune system. Sigma receptors bind a number of compounds, including cocaine, opiates, and neuroleptic drugs. Ligands for sigma receptors have potent immunoregulatory properties including induction of IL-10 expression and suppression of IFN-γ and GM-CSF expression. On p. 3585 , Zhu et al. report that cocaine and two other synthetic sigma1 receptor ligands promoted tumor growth in a murine lung cancer model and up-regulated production of IL-10 at the tumor site. They showed that anti-IL-10 Ab abrogated the tumor-enhancing effect of cocaine and that a sigma1 receptor antagonist was able to block the effects of the sigma receptor ligands on tumor growth. These findings provide insight into the effects of sigma receptor agonists such as cocaine on the IL-10-mediated suppression of tumor immunity and have implications for both prescription drug use and drug abuse.
Generating diversity
The diversity of Ig molecules generated in the host facilitates recognition of a vast array of Ags. The generation of Ig diversity occurs by different mechanisms in different species. In mice and humans, diversity is mainly attained by recombination of a large number of germline gene segments, enhanced by addition or subtraction of nucleotides at junctions between gene segments. In sheep, however, only approximately 20 of the known 90–100 germline Vλ gene segments are found in rearranged DNA. Therefore, Ig diversity in sheep was thought to be predominantly generated by postrearrangement somatic hypermutation. Jenne et al. (p. 3739 ) now report the identification of 64 new Vλ gene segments in the rearranged DNA of sheep and show that eight of these exist in the germline. The authors propose that the Vλ repertoire in sheep is generated through recombination of many more Vλ genes than previously thought, with a concomitant reduction in the role of somatic hypermutation.
Open wide the gates
Thymic dendritic cells (DCs) appear to be the primary mediators of negative selection among developing thymocytes and may function to induce the formation of immunoregulatory thymocytes. However, their developmental origins are unclear. Donskoy and Goldschneider (p. 3514 ) used a combination of unmanipulated, parabiotic, and irradiated mice to study the kinetics and origin of DCs in the steady-state thymus of normal mice. The authors defined two developmentally distinct populations of thymic DCs that were present in approximately equal numbers in the thymus. One population arose intrathymically from bone marrow precursors identified as prothymocytes by staining positive for the CD8α chain. This population entered the thymus in a gated manner and competed with other thymic DC precursors for a limited number of intrathymic niches. These DC cells were most likely derived from a common T/DC precursor, because their appearance paralleled that of T cells; this DC population is considered to act in negative selection of autoreactive T cell clones. The second population of thymic DCs was CD8α/low and appeared to arise extrathymically from partially differentiated DC precursors, perhaps of myeloid origin. The entry of this second population into the thymus was continuous and appeared to provide a pool of DCs possibly involved in the generation of immunoregulatory T cells. The authors speculate that the DCs of nonprothymocyte origin supplement and reinforce the functions of the DCs of intrathymic origin.
Signaling in allergies
Cytokines and chemokines, critical inducers of allergic inflammatory responses, act through a variety of mechanisms. Details of some of the mechanisms and the involvement of STAT proteins in the responses are elucidated in two papers in this issue. Strait et al. (p. 3835 ) focused on the roles of two interleukins, IL-4 and IL-13. The authors demonstrated that the crosslinking of FcεRI by an anti-IgE mAb or of FcγRIII by an anti-FcγRII/RIII mAb induced shock in animals that had been pretreated with IL-4 and IL-13. Using IL-4Rα- and STAT6-deficient mouse strains, they determined that the process required IL-4Rα and STAT6 signaling. Anaphylaxis seen in IL-4-primed mice occurred at a physiological dose of the interleukin and resulted in increased vascular permeability. Raman et al. (p. 3859 ) emphasized the role of STAT4 induction of chemokine production in asthmatic airway hyperreactivity in response to cockroach allergen. They showed that STAT4−/− mice had reduced levels of several critical chemokines (CCL5, CCL11, and CCL17) and less peribronchial inflammation than wild-type controls. Administration of anti-IL-12 Ab during the allergic response in wild-type mice reduced airway hyperreactivity to a lesser degree than in the STAT4−/− mice but had no effect on cytokine or chemokine levels. The results indicate that STAT4 activation and stimulation of chemokine production are important factors in local airway inflammation.
New use for an old drug?
Although autoreactive T cells are known to be involved in the CNS demyelination that occurs in multiple sclerosis (MS), the exact etiology of the disease is poorly understood. A model for studying MS in experimental animals involves the induction of experimental allergic encephalomyelitis (EAE) in rodents, either by injection of myelin basic proteins (MBP) or by adoptive transfer of MBP-reactive T cells. Dasgupta et al. (p. 3874 ) studied the effects of sodium phenylacetate (NaPA), an FDA-approved drug in clinical use for treatment of urea cycle disorders, on the initiation and progression of EAE. The authors found that MBP-primed T cells pretreated with NaPA were unable to proliferate when challenged with MBP. NO production, inducible NO synthase mRNA and protein expression, and NF-κB activation by microglial cells were reduced by NaPA pretreatment of either the microglia or the MBP-primed T cells. Adoptively transferred MBP-primed T cells from NaPA-treated mice were unable to induce EAE in recipient SJL/J mice. Addition of NaPA to the drinking water of mice receiving MBP-primed T cells from mice that had not been treated with NaPA reduced or prevented the clinical onset and progression of EAE. The data suggest that NaPA might warrant investigation as an alternative treatment for human MS.
Upstream control
Transcription of mRNA for the α-chain of FcεRI, the high-affinity receptor for IgE, is stimulated by IL-4 in human mast cells, eosinophils, and monocytes. IL-4 does not have a similar effect on the mouse FcεRI gene. An explanation for these disparate findings comes from Hasegawa et al. (p. 3732 ). The authors found a second promoter in human cells that regulates the expression of FcεRI. This second promoter is IL-4 responsive and is not found in mouse cells. The authors performed luciferase reporter assays on constructs carrying deletion and base-substitution mutations in upstream sequences and EMSAs to map the binding sites of transcription factors Elf-1, PU.1, and YY1. The binding sites of the three factors overlapped in a limited region (distal promoter) more than 19 kbp upstream from the known FcεRI promoter (proximal promoter). Any one of the three factors was able to down-regulate the distal promoter, whereas IL-4 acted on that promoter to increase transcription and intracellular levels of the α-chain protein. In contrast, the proximal promoter was up-regulated by PU.1 and YY1, down-regulated by Elf-1, and unaffected by IL-4. The identification of a second FcεRI α-chain promoter in humans suggests another target for the control of allergic responses.
An ACE up the sleeve
Although inflammatory skin responses frequently accompany the use of dipeptidyl carboxypeptidase angiotensin-converting enzyme (ACE) inhibitors in patients treated for hypertension and myocardial infarction, it is not clear that ACE is directly responsible for the responses. Scholzen et al. (p. 3866 ) used a combination of pharmacology and genetics to study the role of ACE in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). Ear swelling in dinitrofluorobenzene-sensitized C57BL/6J mice was enhanced by systemic administration of the ACE inhibitor captopril before sensitization. Prior treatment with the bradykinin antagonist Hoel40 or with the neurotoxin capsaicin reduced the swelling, indicating that substance P and other neuropeptides were involved in the ACD response. The authors used a genetically engineered mouse model with a heterozygous deletion of somatic ACE to show that ear swelling was more pronounced in dinitrofluorobenzene-sensitized C57BL/6J (ACE+/−) mice than in their wild-type controls (ACE+/+). The ICD response to croton oil was similar in both strains of mice. The conclusion is that ACE plays an important role in controlling ACD but not ICD, and that ACE exerts its action through degradation of substance P and bradykinin.
Long live IgG
Nearly 40 years ago, Brambell suggested that a single receptor might be responsible for perinatal transport and longevity of IgG. To date, β2-microglobulin-deficient mice had been used to assess the function of the so-called neonatal Fc receptor, FcRn. However, the multitude of immunological deficiencies in β2-microglobulin-deficient mice prevented a clear assessment of the role of FcRn. Roopenian et al. (p. 3528 ) defined the role of FcRn by developing FcRn-deficient and human FCRN-transgenic strains of mice that are normal for all immunological parameters tested except FcRn expression. The authors followed maternal IgG transmission after mating FcRn−/− females with FcRn+/− males. Pregnant females were injected i.v. with anti-trinitrophenyl or biotinylated tracer Abs. FcRn−/− neonates had a greater than 190-fold reduction in IgG1 compared with their FcRn+/− littermates. The half-lives of all IgG isotypes were greatly reduced in the FcRn−/− mice compared with wild-type mice, and the FcRn-deficient mice had a diminished ability to mount an IgG response to dinitrophenyl-keyhole limpet hemocyanin. The ability of FcRn to prolong the half-life of IgG may find useful application in the engineering of FcIgG-based therapeutic agents.
Summaries writen by Dorothy L. Buchhagen, Ph.D. and Kaylene J. Kenyon, Ph.D.
- Copyright © 2003 by The American Association of Immunologists
