Immunology highlights from the recent literature

Critical NK cell receptor

NK cells are involved in the innate immune response to pathogens and generally counter infectious agents in a nonspecific manner. However, NK cells appear to respond specifically to certain pathogens, particularly herpesviruses. For example, NK cell–depleted mice are susceptible to MCMV infection. Resistance to MCMV is associated with a dominant locus termed Cmv1. In Science, Yokoyama and colleagues have identified an NK receptor that accounts for this resistance phenotype. They show that the NK cell activation receptor, Ly-49H, is critically involved in resistance to MCMV in vivo. This ITAM-containing receptor functionally resembles B and T cell antigen receptors. Thus, in terms of the innate response to pathogens, NK cells resemble T and B cells more closely than previously appreciated.

Science 292, 934–937 (2001)

TREM-1 in shock

Neutrophils and monocytes-macrophages mediate the innate immune response to bacterial infection via pattern-recognition receptors. In Nature, Colonna and colleagues show that the inflammatory response to microbes is amplified by TREM-1, an activating receptor (similar to those on NK cells) which is abundantly expressed on neutrophils and monocytes. This receptor is also up-regulated on the neutrophils of patients with sepsis, as well as in mice with LPS-induced shock. Blockade of TREM-1 protects mice from both LPS-induced shock and microbial sepsis. TREM-1, therefore, plays a critical role in acute inflammatory responses to bacteria and represents a potential therapeutic target for septic shock.

Nature 410, 1103–1107 (2001)

Evading measles

The mechanisms underlying measles virus (MV)-induced immunosuppression are largely undefined. In the June issue of Nature Medicine, Avota et al. report a newly identified strategy used by measles virus to interfere with T cell activation during immunosuppression. To define the intracellular pathways involved in this immunosuppression, IL-2R signaling was analyzed in a T cell line as well as in primary human T cells. In T cells, protein kinase B, also called Akt, is involved in transducing both anti-apoptotic and proliferative signals. The authors showed that, in contrast to IL-2–dependent activation of Jak-STAT pathways, activation of Akt kinase was impaired after MV contact. They also showed that MV interferes with Akt activation, as expression of catalytically active Akt prevented immunosuppression by MV.

Nature Med. 7, 725–731 (2001)

Unravelling tolerance

Central and peripheral tolerance mechanisms eliminate the majority of autoreactive T cells. However, animal models such as experimental autoimmune encephalo-myelitis (EAE), which is induced by activation of myelin basic protein (MBP)-specific T cells, show that these processes are incomplete. In Immunity, Huseby et al. define the tolerance mechanisms that eliminate the majority of MBP-specific T cells from the periphery. They show that these T cells undergo extensive central tolerance, which is mediated by bone marrow–derived APCs presenting exogenously derived MBP epitopes. The efficiency of tolerance induction is dependent on age and MBP gene dosage, which leads to an age window of susceptibility to EAE that peaks during puberty. Thus, factors regulating expression of self-antigens in vivo can influence susceptibility to autoimmunity.

Immunity 14, 471–481 (2001)

Synaptotagmin and T. cruzi

Trypanasoma cruzi is an intracellular parasite that causes fatal illness in South and Central America. In the Journal of Experimental Medicine, Andrews and colleagues shed light on how this parasite invades its host cell. They showed that synaptotagmin (Syt) VII, a ubiquitously expressed molecule implicated in Ca²⁺-regulated lysosomal exocytosis, is localized on the membranes of intracellular vacuoles containing T. cruzi. Blocking the C₂A domain of Syt VII inhibited cell entry of T. cruzi, but had no effect on the entry of other parasites. In contrast, blocking the C₂A domains of other Syt isoforms had no effect on T. cruzi invasion. These findings indicate that T. cruzi exploits the Syt VII–dependent Ca²⁺-regulated lysosomal exocytic pathway for invading host cells.

J. Exp. Med 193, 1097–1104 (2001)

Artemis in DNA repair

V(D)J recombination of the immunoglobulin and TCR loci is responsible for generating diverse repertoires of antigen receptors. Individuals with mutations in the genes encoding V(D)J recombination enzymes are immunodeficient and may exhibit more generalized defects in DNA repair. One such condition is shown in patients who have increased cellular radiosensitivity (RS-SCID). In Cell, Moshous et al. have identified, on chromosome 10, the human gene Artemis, which is mutated in patients with RS-SCID. In vitro assays with fibroblasts from RS-SCID patients revealed defects in V(D)J coding joint formation, although signal joint formation occurred normally. Functional complementation of this defect was achieved by expression of Artemis in mutant RS-SCID fibroblasts. Thus, Artemis plays a yet-to-be defined role in DNA repair.

Cell 105, 177–186 (2001)

Nature's adjuvant?

Type I interferons play key roles in generating nonspecific immune responses to viral pathogens. Less well known is the role that type I IFNs play in generating antigen-specific immune responses. In Immunity, Tough and colleagues show potent adjuvant activity by type I IFNs in the generation of antibody responses to soluble antigen. Mice treated with these cytokines during immunization showed increased primary antibody production that included all IgG isotypes, and type I IFN–treatment promoted both long-term antibody production and enhanced immunological memory. These responses were absent in mice that lacked type I IFN receptors. The authors also show type I IFN–treatment of dendritic cells is sufficient to elicit these antibody responses after adoptive-transfer. Thus, type I IFNs also play an important role in generating and modulating humoral immune responses.

Immunity 14, 461–470 (2001)