No abstract

Atrial fibrillation (AF) is the most common form of sustained clinical arrhythmia. We previously mapped an AF locus to chromosome 5p13 in an AF family with sudden death in early childhood. Here we show that the specific AF gene underlying this linkage is NUP155, which encodes a member of the nucleoporins, the components of the nuclear pore complex (NPC). We have identified a homozygous mutation, R391H, in NUP155 that cosegregates with AF, affects nuclear localization of NUP155, and reduces nuclear envelope permeability. Homozygous NUP155(-/-) knockout mice die before E8.5, but heterozygous NUP155(+/-) mice show the AF phenotype. The R391H mutation and reduction of NUP155 are associated with inhibition of both export of Hsp70 mRNA and nuclear import of Hsp70 protein. These human and mouse studies indicate that loss of NUP155 function causes AF by altering mRNA and protein transport and link the NPC to cardiovascular disease.

Virus-specific CD8 ؉ T cells emerge after infection with herpesviruses and maintain latency to these persistent pathogens. It has been demonstrated that murine memory CD8 ؉ T-cell precursors specific for acute lymphocytic choriomeningitis virus express interleukin-7 receptor ␣ (IL-7R␣), and IL-7 is involved in maintaining memory populations after the clearance of antigen. To investigate whether human CD8 ؉ T cells reactive toward persistent viruses are maintained similarly, we analyzed IL-7R␣ expression and function on these virus-specific cells. During primary infection, all cytomegalovirus (CMV)-specific CD8 IntroductionAntiviral CD8 ϩ T-cell responses can be divided into 3 distinct phases. In the first phase, CD8 ϩ T cells clonally expand and differentiate into effector T cells that eliminate virus-producing cells. During the contraction phase that follows, most CD8 ϩ T cells die by apoptosis. Finally, in the third phase, the establishment of a CD8 ϩ T-cell memory pool takes place (for a review, see Kaech et al 1 ). The generation of a stable memory T-cell pool is a central feature of the adaptive immune system. On a second encounter with a virus, the immune system will be able to respond faster and more efficiently, thereby limiting cytopathic viral effects. This is achieved because the frequency of antigen-specific cells is greatly enhanced after the primary antigenic challenge, leading to higher numbers of responding T cells. 2 Moreover, on a per-cell basis, memory T cells are better equipped than naive T cells to respond to antigenic challenge because they can respond rapidly by producing in larger quantities important mediators such as interferon ␥ (IFN␥); regulated on activation, normal T-cell expressed and secreted (RANTES); and cytotoxic molecules perforin and granzyme. [3][4][5][6] Several studies have suggested that the expansion and differentiation program is imprinted shortly after antigenic stimulation. 7-9 Moreover, CD4 ϩ T-cell help, either during priming or during the memory phase, is required for CD8 ϩ T cells to be able to mount a proper secondary response. [10][11][12][13] The mechanism behind the development of long-lived memory cells is incompletely understood but depends on the survival of a few antigen-specific cells in the contraction phase. Two recent studies in mice infected with lymphocytic choriomeningitis virus (LCMV) or Listeria monocytogenes showed that during acute infection only a small population (5%-15%) of the effector cells expressed interleukin-7 receptor ␣ (IL-7R␣), whereas in the memory phase all specific CD8 ϩ T cells were IL-7R␣ ϩ . 14,15 The IL-7R␣ ϩ effector cells expressed higher levels of Bcl-2 than their IL-7R␣ Ϫ counterparts. Consistent with their antiapoptotic profile, IL-7R␣ ϩ cells had a superior recall response and showed enhanced proliferation in response to homeostatic signals compared with IL-7R␣ Ϫ cells. This indicated that IL-7R␣ ϩ effector T cells are the cells that survive and develop into long-lived memory CD8 ϩ T cells, which would make IL-7R␣ a us...

OKT3/IL-2 resulted in T cell activation and proliferation, and could stimulate HIV replication in patients having achieved prolonged suppression of plasma viremia. OKT3/IL-2 therapy was toxic and rapidly induced antibodies against OKT3.