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Visualizing Thymic Development
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The Source of Dysfunction
Dysfunctional CD8+ T cells have been observed in many chronic viral infections, but the origin of these cells is not clear. Plesa et al. (p. 5300
) attempted to determine whether dysfunctional CD8+ T cells developed from overstimulated, high-avidity T cells or from incompletely stimulated, low-avidity T cells by using an experimental system that allowed in vivo variation of Ag dose without alteration in viral dose. Whereas low or intermediate Ag doses elicited IFN-
-secreting, functional CD8+ T cells, high Ag doses generated a population of dysfunctional CD8+ T cells that did not secrete IFN-. Upon secondary immunization, dysfunctional CD8+ T cells were maintained in mice receiving high Ag doses but were replaced by functional cells in mice receiving lower Ag doses, suggesting that the dysfunctional cells bore low-avidity TCRs and were therefore unable to compete effectively with higher-avidity functional cells. Through carefully-controlled separation techniques, the authors then isolated the dysfunctional T cell population and compared these cells to the functional population. Supporting the authors’ hypothesis, dysfunctional CD8+ T cells were characterized by low-avidity binding to Ag, broad TCR usage, and lower proliferative capacity than their functional counterparts. These data suggest that dysfunctional cells may be maintained by constant Ag exposure in persistent infections and come to predominate when the high-avidity, functional cells become exhausted.
FLIP-ing T Cells
Studies addressing the involvement of the long isoform of cellular FLICE-like inhibitory protein (c-FLIPL) in T cell activation have yielded conflicting results. These studies mainly utilized overexpression of c-FLIPL, so Zhang et al. (p. 5506
) sought to quell the controversy by developing a conditional knockout mouse lacking c-FLIPL while normally expressing the short isoform (c-FLIPS) of this molecule. In these c-FLIPL–/– mice, the authors observed a complete lack of effector CD8+ T cell development upon infection with Listeria monocytogenes. The development of effector CD4+ T cells producing either Th1 or Th2 cytokines was also greatly reduced in these mice; however, no increase in T cell apoptosis was observed. Compared with T cells from littermate controls, in vitro stimulation of c-FLIPL–/– T cells resulted in a slight delay in activation and a severe defect in proliferation that could not be rescued by exogenous IL-2. Although previous studies have shown that c-FLIPL activates MAPK/AP-1 and NF-
B signaling pathways, these pathways, surprisingly, were activated normally in c-FLIPL–/– T cells. This study begins to clarify the important role of c-FLIPL in T cell activation and differentiation, but questions remain regarding its mechanism of action.
Fly Relish
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B homologue Relish. Although it is known that this pathway is tightly regulated, the mechanisms by which it is inhibited are poorly described. By analyzing genes up-regulated upon Gram-negative bacterial infection, Kleino et al. (p. 5413
) identified a gene involved in Imd pathway regulation, which they named Poor Imd Response upon Knock-in (pirk). pirk was rapidly but transiently up-regulated upon bacterial infection, and its expression was dependent upon Relish activity. In vitro and in vivo experiments involving pirk overexpression or inhibition via pirk RNA interference demonstrated that this molecule specifically suppressed the Imd pathway. Pirk was found to be a cytoplasmic protein directly interacting with both Imd and the cytoplasmic portion of peptidoglycan recognition protein (PGRP)-LC, and the specific regions of Pirk responsible for these interactions were identified. Finally, in vivo overexpression of Pirk reduced fly survival following bacterial infection. Discovery of this novel regulator of Drosophila innate immunity could lead to a better understanding of innate immune activation in vertebrates. Fetal Regulation
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Gut Leakage
In Crohn’s Disease and other cases of gut inflammation, defects are found in the intestinal epithelial barrier. It has been suggested that increased permeability of intestinal epithelial tight junctions (TJ) in these diseases is mediated by proinflammatory cytokines including IL-1β, but the mechanism by which this might occur is unclear. Al-Sadi et al. (p. 5653
) hypothesized that myosin light chain kinase (MLCK), which is known to be important for intestinal TJ permeability, could mediate IL-1β-induced disruption of the epithelial barrier. Indeed, IL-1β caused up-regulation of MLCK in Caco-2 cells that correlated with increased epithelial permeability. Inhibition of MLCK expression or activity prevented this IL-1β-induced increase in TJ permeability, as did siRNA-mediated knock-down of MLCK. The authors further addressed the mechanism of IL-1β-induced TJ permeability by determining that NF-B activation was required for IL-1β-mediated MLCK up-regulation and subsequent epithelial permeability. These meticulous in vitro experiments clarify the mechanism by which IL-1β might modulate permeability of the intestinal epithelial barrier and thus contribute to inflammation in the gut.
Setting SIV Free
Regulatory T cells (Treg) are known to suppress virus-specific immune responses, but much remains to be learned about the role these cells play in the complex pathogenesis of HIV infection. An increase in Treg numbers could prevent effective antiviral immunity, whereas a decrease could lead to T cell hyperactivation and increased viral replication. Qin et al. (p. 5530
) analyzed the Treg population during pathogenic SIV infection in cynomolgus macaques and observed a loss of FoxP3+ Treg in lymph nodes both early and late in SIV infection. Predictably, this decrease in Treg was associated with an increase in T cell activation. Three mechanisms were identified that could contribute to Treg loss. First, decreased expression of TGF-β and IL-2 and increased IFN- expression were observed following SIV infection, suggesting inhibition of Treg differentiation. Treg-expressed CCR4 and CCR7 were also down-regulated, indicating that SIV infection could inhibit Treg homing to the lymph nodes. In addition, the authors observed up-regulation of CXCR3 ligands in SIV infection and found that the CXCR3 ligand CXCL11 could antagonize CCR4 and thus further inhibit Treg migration. This depletion of Treg could allow for increased SIV or HIV replication, suggesting that therapeutic modulation of Treg activity could effectively inhibit HIV pathogenesis.
How to Make a Monocyte
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Summaries written by Jennifer Hartt Meyers, Ph.D.
Related articles in The JI:
B-Independent Pathway
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