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Eradicating solid tumors
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cells are transgenic for SV40 large T Ag. Immunization of RIP1-Tag5 mice at 6 wk of age with Tag protein plus CpG-ODN resulted in 80% survival; immunization at 16 wk resulted in 40% survival. Both protocols were more effective than Tag protein plus CFA. All untreated animals, and animals immunized with Tag protein plus CpG-ODN at 23 wk, died by 35–40 wk. Tag-specific CTL activity was induced in vivo in all Tag protein plus CpG-ODN protocols, but only the early treatment group showed T cell infiltration of islets. Repeated i.v. injections of CpG-ODN alone were unable to prime anti-Tag killer cells in vivo and had no impact on survival. Injected CpG-ODN was taken up by macrophages and led to increased expression of several adhesion molecules on pancreatic endothelial cells. Transfer of ex vivo activated Tag-specific CD8+ and CD4+ T cells with CpG-ODN into 23-wk-old transgenic mice resulted in a 90% survival rate and in T cell infiltration into islets. Tag-specific T cells injected without CpG-ODN did not enter the islets and did not retard tumor growth. The data show that i.v.-injected CpG-ODN is effective in enabling tumor-specific T cells to infiltrate and kill established tumors. Generating anergic T cells
The ability to develop anergic CD4+ T regulatory cells would be important in preventing graft rejection and autoimmune diseases. Chen et al. (p. 5900
) studied the generation of regulatory T cells from female naive monospecific RAG–/– CD4+ T cells that expressed a transgenic TCR specific for a male Ag (Tg). Tg splenocytes transferred into non-Tg male mice of the same background (F>M) did not promote graft-vs-host disease. F>M spleen cells were hyporesponsive to anti-CD3 stimulation compared with spleen cells from non-Tg females injected with Tg female cells (F>F) or from uninjected Tg females. Only the F>M CD4+ T cells were unable to produce IL-2 or proliferate after stimulation with the male Ag and were able to suppress naive monospecific T cell proliferation and IL-2 production. Three percent of the F>M T cells were CD25+, compared with 15% of control F>F T cells, and exhibited up-regulated expression of several other cell surface markers. Forkhead transcription factor foxP3 was not expressed in splenocytes from F>M, F>F, and naive Tg mice. Isolated Tg F1 splenocytes from F>M mice that had received Tg spleen cells from Tg F1 mice, with or without male Tg dendritic cells, did not produce IFN-
when stimulated ex vivo with male Ag. Injected CFSE-labeled unrelated male or female splenocytes, depleted of T cells, survived longer in F>M vs F>F mice. The authors propose that persistent Ag stimulation of CD4+ T cells after adoptive transfer into mice expressing the same Ag renders regulatory T cells generally anergic and suppressive.
A marker of thymocyte positive selection
Cell surface proteins are important in various aspects of the immune system ranging from cell development and maturation to activation. Although many of these proteins have been identified, few are associated with thymocyte positive selection. Han et al. (p. 5931 ) examined the tissue expression pattern of a gene isolated using mRNAs amplified in PMA/ionomycin-activated spleen cells from C57BL/6 (B6) mice. The gene, B and T lymphocyte attenuator (Btla), was found to encode a 306-aa member of an Ig superfamily as well as an alternatively spliced shorter form lacking exon 2. A 305-aa isoform in strain 129 mice had been reported by others. Two mAbs detected BTLA surface expression on single- and double-positive thymocytes but not on double-negative precursors in B6 mice. BTLA also was detected on pro- and pre-B cells in the bone marrow with higher expression levels on more mature cells. All peripheral T and B cells were BTLA+, whereas NK cells had low levels of BTLA expression. LPS activation of B cells reduced BTLA expression, whereas Con A activation of T cells and LPS maturation of dendritic cells greatly increased its expression on those cells. Anti-CD3-induced proliferation of B6 T cells, but not BALB/c T cells, was inhibited by anti-BTLA mAb. BTLA–/– mice had normal B and T cell development, but their T cells were hyperresponsive to TCR-mediated activation. The data indicate that BTLA, a useful marker of thymocyte positive selection, is a negative regulator of TCR-mediated T cell activation.
Evolution of lymphocyte development
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B cells and colitis
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Viral FLIP blocks memory cell development
The poxvirus that is responsible for the human disease molluscum contagiosum contains a Flice-like inhibitory protein (vFLIP) that is known to block apoptosis triggered by death domain-containing TNFRs. The ability of vFLIP to modify immune responses has not been explored. Wu et al. (p. 6313
) generated a transgenic (Tg) strain of C57BL/6 (B6) mice that expresses a vFLIP gene construct in CD4+ and CD8+ T cells. Tg animals had a decrease inCD44–CD25–CD4–CD8– thymocytes and a decrease in CD8+ T cells in the spleen and lymph nodes. Compared with wild-type cells, Tg thymocytes and peripheral CD8+ T cells were highly resistant to anti-CD95 mAb-mediated cell death, but were not resistant to cell death induced through the TCR. CFSE-labeled Tg T cells proliferated poorly in IL-2-supplemented cultures, whereas all markers of activation by CD3 or CD28, except IL-2 responsiveness, were indistinguishable from controls. Tg animals had reduced numbers of splenic CD8+ memory T cells at all ages examined, and the residual memory cells were not able to produce IFN- after stimulation. CD8+ T cells from mice doubly transgenic for vFLIP and an OVA peptide/Kb complex did not expand after OVA challenge of cells injected into a congenic host. B6 mice were resistant to infection with Trypanasoma cruzi, whereas 40% of Tg mice died. Infection of B6 mice with either of two viruses led to expansion of virus-specific CD8+ memory T cells; Tg mice had a lower initial T cell response to the viruses and did not develop memory cells even after virus challenge. The results indicate that vFLIP interferes with memory CD8+ T cell generation by blocking postactivation survival signals.
Bacteria and IFN- production
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) with the intracellular Gram-negative bacterium Chlamydia pneumoniae is associated with increased expression of IFN-
that, in turn, increases expression of IFN-. In their current work (p. 6345
), the authors examined the molecules involved in the response. Toll-like receptor 4 (TLR4)–/– BMM and myeloid differentiation factor 88 (MyD88)–/– BMM infected in vitro were more susceptible to the bacteria and produced less IFN- and IFN- mRNAs than wild-type or other TLR–/– BMM. Levels of phosphorylated STAT1 were diminished in infected BMM lacking receptors for IFN- or IFN-, and IFN- mRNA accumulation was lower in STAT1–/– BMM and IFN- receptor–/– BMM compared with controls. IL-15 mRNA levels were higher in wild-type and IFN- receptor–/– BMM than in BMM that lacked the IFN- receptor or STAT1. Inhibition of the double-stranded RNA-dependent protein kinase or inhibition of I
B- phosphorylation in infected wild-type BMM resulted in decreased IFN- levels and increased bacterial growth, but did not affect levels of IFN- mRNA. The data indicate that macrophages infected with C. pneumoniae induce IFN- and control bacterial growth through interactions among TLR4, MyD88, IFN-, and STAT1. A second pathway, independent of TLR4 and MyD88 but requiring NF-B activation, appears to contribute to increased IFN- production. Summaries written by Dorothy L. Buchhagen, Ph.D.
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