Variegated CD8 cells

Several putative regulatory elements may control lineage-specific regulation of CD8α and CD8β gene expression during T cell development. In Immunity, two groups have deleted different regulatory elements from the CD8 locus. Littman and colleagues showed that deletion of enhancer E8II did not affect CD8 expression in double-positive (DP) thymocytes. Deletion of both E8I and E8II, however, induced variegated expression of CD8, with the appearance of CD4+CD8− thymocytes that were indistinguishable from DP thymocytes. Kioussis and colleagues deleted enhancer E8v, which induced variegated CD8 expression in DP thymocytes and, in peripheral T cells, it diminished CD8 expression. Thus regulatory elements may remodel chromatin structure to facilitate access for factors that are required for the initiation and maintenance of CD8 expression.

Immunity 16, 635–647 & 623–634 (2002)

Adapting apoptosis

Viruses can evade the immune system by interfering with apoptosis. In The EMBO Journal, Boshoff and colleagues show the K7 protein of HSV-8 is structurally and functionally related to ΔEx3, a splice variant of human survivin and a member of the inhibitor-of-apoptosis family. K7 is probably a cellular homolog of ΔEx3 because both contain a mitochondrial-targeting sequence, a BIR domain and a putative BH2-like domain. K7 inhibited apoptosis by forming a protein complex with Bcl-2 and caspase-3 via K7's putative BH2 and BIR domains, respectively. Deletion of the BH2 domain abolished the anti-apoptotic properties of K7. These data suggest that K7 functions as an adapter protein that presents caspase-3 to Bcl-2, enabling this molecule to inhibit caspase activity.

EMBO J. 21, 2602–2615 (2002)

Interfering HIV

RNA interference (RNAi) silences gene expression via short interfering 21–23-mer RNA segments (siRNA) that target homologous mRNA for degradation. In Nature Medicine, Sharp and colleagues report that siRNA technology can be used to inhibit HIV-1 infection. Silencing CD4 expression inhibited viral entry, syncytia formation and reduced free viral titers. Similarly, transfection with siRNA that targeted viral genes, such as p24, also inhibited HIV-1 replication. The p24-siRNA could also reduce virus production post-integration. Thus, RNAi can inhibit both pre- and post-integration steps in the HIV-1 life cycle. As such, siRNA technology could have therapeutic applications for treating HIV and other virus infections. An efficient method of delivering siRNA to cells must now be developed.

Nature Med. 8, 683–688 (2002)

PIP3 marches forward

Phosphatidylinositol-3,4,5-trisphosphate (PIP3) regulates cell polarity and motility. In Nature Cell Biology, Weiner et al. and Wang et al. show that the induction of PIP3 in response to a chemotatic gradient results in a positive feedback loop that is dependent on both phosphatidylinositol-3 kinase and the Rho family of GTPases. The polarization of PIP3 depends on actin polymerization. Two related papers in Cell by Iijima et al. and Funamoto et al. show that the enzyme that degrades PIP3, PTEN, is excluded from the leading edge and is localized to the lateral and posterior membranes of the migrating cell. Together, this reinforcement of the PIP3 signals within the cells helps to maintain polarity and motility as cells travel up the chemoattractant concentration gradient.

Cell 109, 599–610 & 611–623 (2002);

Nature Cell Biol. July, 2002 (doi:10.1038/ncb810) & July, 2002 (doi: 10.1038/ncb811)

Seeing is believing

Much of our understanding in cell-cell interactions is derived from the imaging of cell suspensions in vitro. However, in the June issue of Science, Miller et al. and Stoll et al. use two-photon microscopy and laser scanning confocal microscopy, respectively, to visualize dynamic interactions of cells in intact, albeit explanted, organs. The two different microscopy methods and other experimental differences resulted in contrasting conclusions in terms of how T cells and dendritic cells interact. In the same issue of Science, Buosso et al. use two-photon microscopy to visualize the interaction between thymocytes and stromal cells during positive selection in the thymus and show that the two different models of T cell–MHC interaction (dynamic versus stable) may both occur in vivo.

Science 296, 1869–1873, 1873–1876 & 1876–1880 (2002)

Active “split” tolerance

True immunological tolerance is the inability of antigen-specific T cells to attack self, despite their persistent presence in the periphery. In the Journal of Experimental Medicine, Greenberg and colleagues show true tolerance was actively maintained in vivo for antitumor-specific CD8+ T cells. Peripheral CD8+ T cells from thymectomized TCR-transgenic mice expressing viral tumor transgenes in the liver up-regulated expression of activation markers and Bcl-2, but did not have autoimmune disease. The CD8 cells retained their effector capacity, as measured by in vitro stimulation for cytokine production and perforin lysis of target cells. However, they did not divide or produce IL-2 in response to antigen. These data point to multiple mechanisms that must operate to establish and maintain tolerance in vivo.

J. Exp. Med. June 17, 2002 (doi:1084/jem.20011063)

Mixed signals

The adaptor protein LAT transmits multiple signals from the T cell receptor. LAT couples pre-TCR or TCR signals to activation and survival by connecting to both the Ras-Erk and the phospholipase C (PLC) pathways. Aguado et al. and Sommers et al. report in Science that specific mutation of Tyr136 in the LAT cytoplasmic domain uncouples TCR activation from the PLC-γ1, but not the Erk, pathway. CD4+CD8+ thymocyte development was severely reduced in “knock-in” mice expressing the single Y136F mutation. However, adult mice exhibited increased numbers of peripheral T cells, which were skewed towards activated TH2 CD4 subsets and showed secondary autoimmune manifestations (increased IgG and IgE and eosinophilia). Thus, LAT's bridge to the PLC-γ1 pathway plays a positive role at the CD4−CD8−→CD4+CD8+ checkpoint and transmits negative signals that prevent excessive TH2 CD4 activation and survival in the periphery.

Science 296, 2036–2040 & 2040–2043 (2002)