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Mast cells and chronic asthma
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Selectins in parasite immunity
T cell migration to sites of inflammation is facilitated by the expression of selectins on endothelial cells. Yet the role of selectins in the development of protective immunity is unknown. Zaph and Scott (p. 4726
) found that expression of P- and E-selectin ligands (PESLs) on CD4+ T cells from draining lymph nodes (dLN) of mice infected with the parasite Leishmania major 14 days earlier was dependent on IL-12-induced expression of the enzyme 
(1,3)-fucosyltransferase VII. Treatment of mice with anti-IL-12 Ab before infection significantly reduced the number of T cells expressing PESLs. In vitro stimulation of dLN cells from infected mice with soluble L. major Ag resulted in a higher frequency of activated T cells with increased levels of PESLs and IFN-
expression compared with medium-treated controls. Although E-selectin-/- and P-selectin-/- mice infected with L. major developed lesions identical to wild-type animals, mice deficient for both selectins had lesions approximately one-half the size seen in infected wild-type animals. Mice lacking both selectins had delayed-type hypersensitivity responses one-half as intense as those of wild-type mice although they were as effective as wild-type mice in resolving secondary infections. The results suggest that endothelial selectins are responsible for infection-induced pathology but do not play a role in host immunity.
Preventing arthritis
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and IL-1
resulted in down-regulation of IL-6, IL-8, matrix metalloproteinases, and macrophage inflammatory protein-3 only in the p21Cip1-transfected cells. p21Cip1 also down-regulated the activity of the NF-
B and AP-1 transcription factors that control the suppressed inflammatory mediator genes. Coprecipitation of c-Jun N-terminal kinase, the activator of AP-1, with p21Cip1 from p21Cip1-expressing RSF stimulated by LPS showed that p21Cip1 directly down-regulated those kinase pathways. It appears that p21Cip1 mediates its anti-inflammatory and bone-protective effects by inactivation of intracellular signaling pathways. Trafficking in the thymus
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MyD88 and bacterial infections
The adapter molecule, myeloid differentiation factor 88 (MyD88), mediates signal transduction by Toll-like receptors (TLR). TLR2 and TLR4, two members of the TLR/IL-1R superfamily, have been shown to affect immune reactions to mycobacteria. Mycobacterium avium infection in mice deficient in MyD88, TLR2, and TLR4 was studied by Feng et al. (p. 4758
). All MyD88-/- mice died 9–14 wk postinfection (p.i.) and all TLR2-/- mice died 16–22 wk p.i. In contrast, all wild-type and most TLR4-/- mice survived for 25 wk p.i. Bacterial titers were significantly higher in liver and lungs of the MyD88-/- and TLR2-/- mice compared with the other strains, and the livers of MyD88-/- and TLR2-/- mice had fewer neutrophils. Hepatic granulomas in MyD88-/- mice contained large numbers of bacilli, whereas those in wild-type mice did not. Moreover, pulmonary granulomas in the MyD88-/- animals, but not those in the other strains, were large and necrotic. MyD88-/- macrophages did not produce IL-6, TNF, and IL-12p40 when challenged in vitro with M. avium; TLR2-/- macrophages produced reduced levels of the same cytokines compared with TLR4-/- or wild-type macrophages. IFN- production was reduced in the livers of only the MyD88-/- mice two weeks p.i. The increased susceptibility of MyD88-/- and TLR2-/- mice to M. avium infection suggests that MyD88, and to a lesser extent, TLR2 are required for host resistance.
Thymocyte selection by PD-1
The programmed death receptor 1 (PD-1) is expressed on thymocytes; PD-1-deficient mice develop autoimmune diseases. It is not clear, however, that PD-1 plays a direct role in thymic selection of developing T cells. Blank et al. (p. 4574 ) found that spleens of 2C TCR Tg/RAG2-/-/PD-1-/- mice contained substantially higher levels of CD4-CD8- double-negative (DN) lB2+ T cells than PD-1+/+ controls. The DN cells did not produce IL-2 or proliferate when stimulated with tumor cells but responded to non-CD8-dependent stimuli such as anti-CD3/anti-CD28 mAbs. PD1+/+ thymocytes expressed PD-1 at all stages of development. Increased binding of Annexin V to 1B2- CD4+CD8+ double-positive thymocytes from the PD-1-/- mice indicated that loss of this population was due to increased cell death. Peripheral PD-1-/- DN cells had lost heat-stable Ag expression indicating they had undergone positive selection in the thymus. This conclusion was supported by a 50% reduction in the number of DN T cells in irradiated H-2k mice injected with T-depleted bone marrow cells from H-2b PD-1-/- mice compared with the number seen in syngeneic H-2b recipients. The results show that PD-1 can act as a negative modulator of TCR signaling and can influence thymic selection.
Macrophage receptor Dectin-1
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-glucan component of microbial cell walls. Induction of this receptor is important in the innate response to fungal pathogens. Willment et al. (p. 4569
) found that surface and mRNA expression of Dectin-1 in resident macrophages (res-M
) was increased within 4 h after treatment with IL-4 and IL-13 and by 24 h after treatment with GM-CSF and TGF-. IFN- had little effect at 4 h but antagonized the IL-4 induction of Dectin-1 at 24 h. Dexamethasone, IL-10, and LPS treatment led to reduced expression of the receptor at 24 h. Similar responses were seen with thioglycollate-elicited inflammatory M (thio-M), although TGF- had no effect on Dectin-1 expression and IFN- did not antagonize IL-4 at 24 h. Treatment of M with laminarin, an inhibitor of Dectin-1, decreased binding of -glucan-rich zymosan. Pretreatment of cells with the Dectin-1 antagonist, glucan phosphate, inhibited zymosan-induced TNF- production completely in res-M but only partially in thio-M. IL-4 production was enhanced in the res-M but suppressed in the thio-M. Pretreatment with IFN- greatly enhanced TNF- production in response to zymosan in both M populations, but Dectin-1 was implicated only in the response in thio-M. The authors conclude that cytokines can modulate Dectin-1 expression on primary M and, thus, influence the response to fungal infection. Summaries written by Dorothy L. Buchhagen, Ph.D.
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