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SAXSy MBL Conformations
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3-fold larger than oligomers in solution. The authors propose that the increase is due to unbending of the stalk curvature after CRD binding to surface mannosamine. Protein Transfer to Kill Tumors
Studies show that immunostimulatory or inhibitory molecules are able to increase antitumor immunity. To overcome the limited efficacy of these treatments applied singly, Liu et al. (p. 3301
) used their protein transfer method to inject mouse tumors with two chemotactic molecules to increase infiltration of neutrophils, dendritic cells (DCs) and T cells, followed by injection with two costimulatory molecules to increase functions of DCs and T cells. Injection with the two chemotactic molecules or with all four proteins increased infiltration of neutrophils and CD4+ and CD8+ T cells compared with controls, whereas an increase in DCs was seen only after injection with the four proteins. Injection with the chemotactic proteins or all four proteins reduced intratumoral regulatory T cells by >80%. The cytokine profile of cells isolated from tumors treated with all four proteins was predominantly Th1 with high IL-12 and IFN-
and low IL-10 levels. Although growth of some established lymphomas was delayed or occasionally regressed after injection with either the chemotactic or costimulatory molecules, complete tumor regression was seen in 65% of tumors treated with all four pro-teins. Mice whose tumors regressed were protected against i.p. tumor challenge 2 or 6 mo later, and their CTLs had strong in vitro activity against the tumor cells 4-6 wk after rechallenge. The authors demonstrate that a combination of defined amounts of immunostimulatory molecules delivered to a mouse lymphoma by protein transfer enhances antitumor responses.
Role of IGF-1R in Graves’ Disease
Smith and collaborators reported expression of insulin-like growth factor-1R (IGF-1R) by a large fraction of fibroblasts from patients with autoimmune Graves’ disease (GD). However, it is not known how lymphocytes are recruited to the orbit to cause thyroid-associated ophthalmopathy (TAO). In a follow-up to their earlier work, Douglas et al. (p. 3281 ) in the Smith laboratory measured substantially higher expression of IGF-1R on peripheral blood and orbital CD4+ and CD8+ memory T cells from GD patients vs controls. In contrast, controls and a GD patient had similar high IGF-1R levels on bone marrow T cells. Anti-CD3 Ab plus IGF-1, or an IGF-1 analog that selectively activates IGF-1R, expanded IGF-1R+ T cells in culture greater than GD T cells exposed to anti-CD3 Ab alone. T cells from healthy donors did not respond to IGF-1 or the analog. Only GD T cells proliferated in response to GD-IgG, and IGF-1 reduced apoptosis only in GD T cells. The authors conclude that up-regulation of IGF-1R is responsible for proliferation and reduced apoptosis of inflammatory memory T cells recruited to orbital tissue in patients with GD.
FcRIIA/Lipid Raft Association
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RIIA is known to associate with lipid rafts to initiate a series of intracellular signaling events, the roles played by different receptor domains have not been delineated. García-García et al. (p. 3048
) generated human FcRIIA mutants defective in palmitoylation (Pal–), in phosphorylation of the ITAM (ITAM–), in the cytoplasmic domain (Cyt–), or in the transmembrane domain (TM–). Stable transfectants were created by introduction of these mutants into human cells lacking endogenous FcRIIA. Analysis of detergent-resistant membrane (DRM) fractions from receptor-activated cells showed that ITAM–, Pal–, Cyt–, or most of the TM– mutants were as capable as wild-type FcRIIA of associating with lipid rafts. One TM– mutant was not found in the DRM fraction, and two TM– mutants were found in both the nonlipid raft and DRM fractions after activation. All TM– mutants induced Syk activation, but two had kinetics slightly different from that of the wild-type receptor. DRM association was required for activation of NF-
B and for reduction in ERK phosphorylation; NF-B activation and ERK phosphorylation were greater in mutants constitutively associated with DRM. Phagocytosis was efficient in wild-type FcRIIA-transfected cells but was at lower levels in cells transfected with constitutively DRM-associated mutants. Phagocytosis in all cells was reduced in the presence of a Syk inhibitor. The authors conclude that only the TM domain of human FcRIIA regulates its association with lipid rafts following ligand-induced cross-linking. Investigating CIA Loci
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Understanding Immunodominance
Factors that determine immunodominance hierarchies of primary and secondary virus-specific CD8+ T cell responses are not fully understood. However, suggestions that TCR repertoire size and Ag load are important prompted Thomas et al. (p. 3091 ) to look at compensatory expansion of CD8+ T cells of other specificities in the absence of dominant epitopes in influenza virus infection. C57BL/6 mice infected i.p. with influenza virus were boosted intranasally (i.n.) 6 wk later with a serologically distinct influenza virus strain. Mice primed/boosted with viruses containing double knockouts (DKO) of two major MHC class I epitopes generated increased splenic CD8+ T cell responses specific for a third epitope after a secondary DKO virus challenge. Mice primed/boosted with triple knockout (TKO) viruses did not have an enhanced recall response. Mice infected i.n. with the TKO variant cleared the infection more rapidly and had higher virus-specific serum Ig levels 5 days later, whereas TKO-infected IgM–/– or MHCII–/– mice had worse clinical symptoms and lower virus clearance than controls infected i.n. with DKO or wild-type virus. However, only DKO virus-infected IgM–/– or MHCII–/– mice developed compensatory responses to other epitopes after DKO virus challenge. Secondary responses to minor epitopes were seen in both DKO and TKO virus-infected MHCII–/– animals. The authors suggest a complex interplay between CD8+ T cell-mediated and humoral immunity in the development of immunodominance hierarchies during influenza virus infections in mice.
Aire-Regulated MTEC Development
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
RIIA Alter Its Association with Lipid Rafts: Implications for Receptor Signaling
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