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TLR2 and fungal infection
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, but only 20–30% less TNF-
, IL-1
, and IL-6 from TLR2-/- cells than from control cells. Uninfected TLR2-/- mice had half the number of CD4+CD25+ T regulatory (Treg) cells as uninfected wild-type mice. Wild-type Treg cells incubated with a TLR2 ligand had increased survival times. Depletion of Treg cells in TLR2+/+ mice with an anti-CD25 mAb resulted in a 10-fold decrease of fungal outgrowth in kidneys 7 days postinfection. The data are interpreted to suggest that C. albicans interacts with TLR2 to induce immunosuppression through production of IL-10 by Treg cells. TCR architectural changes
The TCR complex is down-modulated following ligation with the MHC:peptide complex. Although rapid removal of the ligated TCR is required for continued serial triggering and signal amplification, the molecular mechanisms involved are unknown. La Gruta et al. (p. 3662
) transfected CD3
genes into murine T cell hybridomas lacking endogenous CD3. Expression of the transgene restored TCR expression. A FLAG peptide attached to the NH2-terminal extracellular portion of one of the transgenes bound more anti-FLAG Ab at 5 h following down-modulation induced by stimulation of T cells with Ag-pulsed B cells than unstimulated transgenic cells. Biotinylated free and TCR-associated CD3 were increased in immunoprecipitates from stimulated cells, whereas there was little increase in biotinylation of intact CD3 complex on the cell surface. Mutation of the extracellular domain of CD3 at lysine 9, a possible target for biotinylation, did not alter the biotinylation pattern. Pretreatment of transgenic hybridomas with an inhibitor of Src family protein tyrosine kinases decreased TCR down-modulation and abrogated CD3 biotinylation. The data indicate that MHC:peptide ligation results in a phosphorylation-dependent architectural change in the TCR:CD3 complex that exposes the CD3 NH2 terminus and leads to dissociation of the CD3 dimer. The authors suggest that the change allows T cells to recognize and degrade ligated TCR.
B cell cytokine profiles
Optimal proliferation and differentiation of B cell receptor (BCR)-stimulated B cells occurs in response to CD40 interacting with its ligand, CD40L, on activated T cells. B cells also can proliferate extensively following CD40-CD40L interactions in the absence of BCR stimulation and minimally following BCR engagement alone. Duddy et al. (p. 3422
) used an ex vivo system to profile the cytokines released by human B cells under these and other conditions. They found that a 1:15 ratio of CD40L-transfected L cells:B cells was optimal for proliferation. CD40 stimulation alone with the transfected L cells resulted in high levels of IL-10 and IL-6 and minimal amounts of TNF- and lymphotoxin (LT) compared with unstimulated cells. IL-10 levels were suppressed and TNF-, LT, and IL-6 levels were increased greatly by BCR and CD40 dual stimulation. Staggered dual stimulation (BCR followed by CD40) eliminated IL-10 and further enhanced production of the other cytokines. Production of TNF-, LT, and IL-6 was dose-dependent on BCR cross-linking Ab. However, IL-10 secretion was complex. High levels were expressed in response to BCR cross-linking Ab alone; but CD40-stimulated IL-10 production, inhibited by low doses of the Ab, could be amplified by high doses of Ab. The data suggest that B cells play an active role in regulating local immune responses through patterns of B cell cytokines that vary with the type of stimulation.
TCR plasticity
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OX40-OX40L interactions in T cells
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CD93 and phagocytosis
Although CD93, expressed on myeloid and endothelial cells, platelets, and microglia, is identical with the human receptor for C1 (C1qRp), there is no evidence that C1q and CD93 interact directly. Norsworthy et al. (p. 3406 ) disrupted the mouse CD93 gene by homologous recombination using a targeting vector that generated a deletion within exon 1. CD93-/- mice were fully viable and fertile, and the maturation and distribution of bone marrow cells was comparable to that of wild-type mice. Thioglycollate-elicited macrophages from wild-type and CD93-/- mice incubated in vitro with C1q equally phagocytosed RBCs coated with C3 or with IgG2a. RBCs precoated in vitro with IgG1 or IgM before i.p. injection into wild-type and CD93-/- mice were phagocytosed to the same extent. CD93-/- mice had a significant decrease in the percentage of macrophages ingesting i.p.-injected apoptotic T cells compared with wild-type controls. Apoptotic cells preopsonized with serum containing C1q were taken up equally by wild-type and CD93-/- macrophages in vitro. However, both types of macrophages had impaired phagocytic activity for cells preopsonized in serum deficient in C1q. Leukocyte recruitment into the inflammatory peritoneum was comparable in both CD93-/- and wild-type mice. The authors conclude that CD93 may not be a true C1q receptor but, rather, is involved in phagocytosis of apoptotic cells by peritoneal macrophages in vivo.
Tumor cell gangliosides
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B as well as increased susceptibility to apoptosis. Although soluble gangliosides from RCC cells were found to be responsible for these phenomena, the mechanisms involved are unknown. Thornton et al. (p. 3480
) detected, by supershift assay, two B binding complexes in Jurkat T cells stimulated in vitro with PMA/ionomycin; the complexes, comprised of RelA and p50 subunits, were absent from activated T cells cocultured with RCC cells but present in activated T cells cocultured with control smooth muscle cells. Overexpression of recombinant RelA reversed both the decrease in intracellular levels of RelA, p50, and an anti-apoptotic protein, Bcl-xl, and the increase in apoptosis following 48 h of coculture with each of three RCC cell lines. Cell lysates of RCC-exposed Jurkat, but not control, cells degraded recombinant RelA protein. T cells cocultured with RCC in the presence of caspase inhibitors were protected from apoptosis and their lysates lost the degradative capability. Pretreatment of RCC with a ganglioside inhibitor before coculture with Jurkat cells resulted in normal levels of the NF-B protein subunits and one-tenth the amount of apoptosis compared with T cells exposed to untreated RCC. The authors demonstrate that the gangliosides produced by tumor cells induce T cell apoptosis by caspase-mediated degradation of NF-B subunits. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
B in T Cells by Gangliosides Expressed on Renal Cell Carcinomas
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