| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
CCL21 and influx of lymphocytes into the thyroid
|
–/– background but not in thyroids of nontransgenic controls. The experiments show that recruitment of T and B lymphocytes into the thyroid depends on CCL21 and its receptor CCR7 and is independent of L-selectin, HEVs, and lymphotoxin . B7 is required to induce and maintain tolerance
Effective T cell activation occurs when Ag is presented along with a costimulatory signal. Although lack of costimulation is thought to result in clonal anergy, this has not been definitively proven. Lohr et al. (p. 5028 ) adoptively transferred CFSE-labeled CD4+ T cells from mice transgenic for an OVA peptide-specific TCR into wild-type mice. The cells proliferated weakly in vivo when the mice were immunized with LPS-treated B7–/– mature bone marrow-derived dendritic cells (DCs) incubated with OVA peptide. The response to similarly treated wild-type DCs was strong. However, T cells that had been primed with B7–/– DCs proliferated when stimulated ex vivo with OVA peptide. There was less expansion of CFSE-labeled T cells in B7–/– mice transgenically expressing soluble OVA peptide than in wild-type recipients expressing the same peptide. Injected cells were purified by cell sorting and restimulated ex vivo with OVA peptide; cells from both recipients were hyporesponsive. However, in vivo immunization of the recipients with OVA peptide-pulsed wild-type DCs led to loss of tolerance only in the B7–/– mice. Mice were generated that were doubly transgenic for an OVA peptide-specific TCR and either a soluble OVA peptide or a membrane-bound OVA peptide on a B7–/– background. CD4+CD25+ T cell numbers were higher in the mice expressing the membrane-bound OVA peptide, although both strains had fewer CD4+CD25+ T cells with suppressive function compared with the TCR transgenic wild-type parent. The authors conclude that B7 is required both to induce and maintain tolerance.
Caspase regulation of T cell proliferation
Although caspases are recognized as regulators of cytokine secretion and as inducers of apoptosis, they also play an undefined role in activation-induced proliferation of T cells. Falk et al. (p. 5077
) found that a broad-spectrum caspase inhibitor reduced the response to anti-CD3 mAb stimulation of human PBMCs and, to a lesser extent, of purified human T cells. Stimulation of PBMCs or T cells in the presence of the caspase inhibitor resulted in decreased intracellular levels of active caspase-8 and caspase-3 as visualized in immunofluorescence using antisera against the active forms of the caspases. The caspase inhibitor abolished the up-regulation of all cell cycle-associated proteins studied (including cyclins and cyclin-dependent kinases) and reduced secretion of IL-2 and expression of IL-2R in stimulated PBMCs and T cells; there was no increase in apoptosis. Caspase inhibition of T cell proliferation was partially reversed by addition of exogenous IL-2, but not IL-1
or IL-18. The caspase inhibitor reduced NF-
B activation, IL-2 promoter-dependent luciferase activity, and activities of other transcription factors in a stimulated human T cell line lacking caspase-8. The caspase inhibitor also reduced secretion of TNF from LPS-stimulated purified primary human monocytes. The authors conclude that caspases regulate activation of cell cycle proteins and transcription factors needed for induction of the IL-2/IL-2R system in human T cells following TCR stimulation.
Regulating mast cell activation
|
-hexosaminidase and TNF--induced cytotoxicity were reduced in LAT–/– and all mutant LAT BMMCs compared with wild-type cells; LAT-YFFF BMMCs had the lowest TNF- response. IgE-induced up-regulation of IL-6, IL-13, and TNF- mRNAs was reduced in all except wild-type cells. Ca2+ mobilization and phosphorylation of MAPKs also were decreased in all except wild-type BMMCs, with Y136 most critical for the Ca2+ response and the other three Ys more critical for the kinase phosphorylation. Similar LAT knockin populations were expanded from peritoneal cell-derived mast cells (PCMCs). LAT–/– PCMCs showed more severe impairment of -hexosaminidase, TNF- release, and MAPK phosphorylation than LAT–/– BMMCs after IgE or IgG, plus Ag, stimulation. Enzyme release was restored in LAT-YFFF, partially restored in LAT-FFFF, but absent in LAT-FYYY PCMCs. The authors interpret the data to indicate positive and negative regulation of BMMCs and PCMCs by LAT and differential contributions of the four distal Ys. Dendritic cell selection of CD8+ T cells
|
2m cDNA under control of the CD11c promoter; the transgenic animals expressed H-2Kb only on thymic DCs. Transgenic and MHCI–/– mice had one-tenth the number of CD8+ T cells in their thymi and lymph nodes as wild-type mice. The numbers of CD4+CD8+ T cells and CD4+ T cells were equivalent to those of controls. Chimeras, created by injecting MHCI+ bone marrow into MHCI–/– recipients, contained elevated CD8+ T cells compared with MHCI–/– mice receiving MHCI–/– or transgenic bone marrow. Transgenic mice had a 2-fold higher percentage of TCRV5+CD8+ T cells compared with MHCI–/– mice. Mice transgenically expressing 2m only on their thymic cortical epithelium had elevated frequencies and numbers of CD8+ T cells compared with MHCI+ animals; CD8+ T cell numbers were reduced to wild-type levels in mice doubly transgenic for expression of MHCI on thymic cortical epithelial cells and thymic DCs. In vivo cytotoxicity assays showed that MHCI–/– splenocytes were specifically rejected in MHCI+ hosts, and control MHCI–/– hosts specifically rejected MHCI+ splenocytes. However, single- or double-transgenic hosts did not reject either MHCI+ or MHCI–/– splenocytes. The data exclude DCs as inducers of positive CD8+ T cell selection in vivo but suggest that they can tolerize self-reactive CD8+ T cells.
V
1+ 
T cells, Th1 cytokines, and immunity to bacterial infection
Primary participants in host defenses against microbial infections are T cells, especially those bearing an invariant V1 TCR. Yet little is known about how these cells function to protect the host. Tagawa et al. (p. 5156
) found fewer bacteria in the peritoneal cavities of wild-type mice than of V1–/– mice 3 days after i.p. infection with Escherichia coli. The proportion of T cells in peritoneal exudate cells (PECs) from infected wild-type mice was nearly twice that from mutant mice by day 2 postinfection (p.i.), although both groups had increased numbers of T cells by day 1 p.i. compared with uninfected controls. In mutant vs wild-type mice, numbers of macrophages, but not lymphocytes, were significantly reduced in PECs by day 2 p.i., and numbers of polymorphonuclear leukocytes were slightly reduced. Enriched T cells from wild-type mice produced higher levels of CCL3 and CCL5 in response to in vitro activation by TCR triggering than V1–/– mice. However, only CCL3 levels were elevated in lavage fluid of the peritoneal cavity in wild-type mice compared with mutant mice 2 days p.i. Wild-type mice injected with anti-CCL3 mAb just before, and 24 h after, infection with E. coli had reduced numbers of T cells and macrophages in PECs at day 1 p.i. compared with similarly treated wild-type mice; injection of anti-CCL5 mAb had no effect. Anti-CCL3 mAb-treated mice also had a significant increase of E. coli in their peritoneal cavities compared with the other groups of animals. The data suggest that V1+ T cells produce CCL3 that attracts macrophages to the sites of E. coli infection, thus bridging a gap between protection by neutrophils and macrophages.
Regulating cAMP levels in lipid rafts during TCR triggering
|
) and CD28, from unstimulated T cells accumulated high levels of cAMP when stimulated with anti-CD3/anti-CD28 in the presence of Mg2+/ATP. Lipid rafts from cells stimulated with anti-CD3/anti-CD28 had high levels of Gs, -arrestin, and PDE4, whereas rafts from unstimulated T cells had high levels of adenyl cyclase inhibitory G protein (Gi). Rafts from T cells stimulated with anti-CD3 alone had low levels of -arrestin and PDE4 activity. Incubation of lipid rafts with Abs that blocked Gs function reduced poststimulation cAMP levels, whereas incubation with Abs that blocked Gi function increased cAMP levels. TCR-induced activation of protein kinase A activity in cells treated with anti-CD3 Ab was increased by overexpression of a transfected PDE4-expressing plasmid. Overexpression of either PDE4 or -arrestin, or inhibition of protein kinase A, in TCR-stimulated cells led to increased IL-2 and IFN- production. The data suggest that cAMP levels in CD3/CD28-activated T cells are controlled by the recruitment to lipid rafts of a PDE4/-arrestin complex that down-modulates inhibitory cAMP signals. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
1+ T Cells Producing CC Chemokines May Bridge a Gap between Neutrophils and Macrophages in Innate Immunity during Escherichia coli Infection in Mice
| ||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
