HIV vaccination: turning the spotlight on effector memory T cells as mucosal gatekeepers

The accumulating failures in HIV vaccine development demonstrate that the immunization approaches used so far are insufficient to reproduce the naturally occurring immunity that controls the virus in long-term non-progressors, HIV controllers, and continuously exposed sex workers. They also underscore the desperate need for new approaches in the design of more effective vaccination protocols. Recent findings might have brought us closer to that goal by providing proof of concept for a novel preventative HIV vaccine by establishing CD8 effector memory T cells within the mucosal sites of transmission

Simple, efficient in vitro synthesis of capped RNA useful for direct expression of cloned eukaryotic genes

A simple and efficient method for direct in vitro synthesis of capped transcripts of cloned eukaryotic genes is described. As an example capped transcripts were made from a plasmid containing the human fibroblast interferon gene cloned under the control of a prokaryotic promoter. These transcripts were translated in vivo in Xenopus laevis oocytes and in vitro in reticulocyte and in wheat germ cell-free protein synthesizing systems

Comparison of exon 5 sequences from 35 class I genes of the BALB/c mouse

DNA sequences of the fifth exon, which encodes the transmembrane domain, were determined for the BALB/c mouse class I MHC genes and used to study the relationships between them. Based on nucleotide sequence similarity, the exon 5 sequences can be divided into seven groups. Although most members within each group are at least 80% similar to each other, comparison between groups reveals that the groups share little similarity. However, in spite of the extensive variation of the fifth exon sequences, analysis of their predicted amino acid translations reveals that only four class I gene fifth exons have frameshifts or stop codons that terminate their translation and prevent them from encoding a domain that is both hydrophobic and long enough to span a lipid bilayer. Exactly 27 of the remaining fifth exons could encode a domain that is similar to those of the transplantation antigens in that it consists of a proline-rich connecting peptide, a transmembrane segment, and a cytoplasmic portion with membrane-anchoring basic residues. The conservation of this motif in the majority of the fifth exon translations in spite of extensive variation suggests that selective pressure exists for these exons to maintain their ability to encode a functional transmembrane domain, raising the possibility that many of the nonclassical class I genes encode functionally important products

NIK-dependent RelB Activation Defines a Unique Signaling Pathway for the Development of Vα14i NKT Cells

A defect in RelB, a member of the Rel/nuclear factor (NF)-κB family of transcription factors, affects antigen presenting cells and the formation of lymphoid organs, but its role in T lymphocyte differentiation is not well characterized. Here, we show that RelB deficiency in mice leads to a selective decrease of NKT cells. RelB must be expressed in an irradiation-resistant host cell that can be CD1d negative, indicating that the RelB expressing cell does not contribute directly to the positive selection of CD1d-dependent NKT cells. Like RelB-deficient mice, aly/aly mice with a mutation for the NF-κB–inducing kinase (NIK), have reduced NKT cell numbers. An analysis of NK1.1 and CD44 expression on NKT cells in the thymus of aly/aly mice reveals a late block in development. In vitro, we show that NIK is necessary for RelB activation upon triggering of surface receptors. This link between NIK and RelB was further demonstrated in vivo by analyzing RelB+/− × aly/+ compound heterozygous mice. After stimulation with α-GalCer, an antigen recognized by NKT cells, these compound heterozygotes had reduced responses compared with either RelB+/− or aly/+ mice. These data illustrate the complex interplay between hemopoietic and nonhemopoietic cell types for the development of NKT cells, and they demonstrate the unique requirement of NKT cells for a signaling pathway mediated by NIK activation of RelB in a thymic stromal cell

Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation

Constitutive NF-κB activation in IECs induces inflammatory cytokines and chemokines in the lamina propria, but does not result in overt tissue damage unless acute inflammatory insults are present, causing TNF-dependent destruction and barrier disruption

Transcriptional reprogramming of mature CD4 + helper T cells generates distinct MHC class II- restricted cytotoxic T lymphocytes

2 8 1 CD4 + T cells are commonly classified as 'helper' T cells on the basis of their roles in providing help to promote or dampen cellular and humoral immune responses. In contrast, CD8αβ + cytotoxic T lympho cytes (CTLs) provide direct protective immunity by killing infected or transformed cells. The helper T cell program is initially induced during thymic development, during which thymocytes expressing a major histocompatibility complex (MHC) class II-reactive T cell antigen receptor (TCR) develop into the CD4 + helper T cell lineage, whereas thymocytes with specificity for MHC class I differentiate into the CD8 + CTL lineage. The functional programming, which coincides with but does not depend on the MHC restriction or expression of the coreceptor CD4 or CD8αβ, is controlled by the action and counter action of key transcription factors. Together with Tox and GATA3, the helper T cell transcription factor ThPOK (cKrox; encoded by Zbtb7b (called 'Thpok' here)) first induces the CD4 + helper T cell fate and prevents thymocytes from differentiating into CD8 + CTLs 1-6 . Runx3, a member of the Runx family of transcription factors, has the opposite effect and terminates CD4 expression while promoting differentiation into the CTL lineage That lineage separation, however, is not all encompassing, and reports have repeatedly indicated the presence of CD4 + T cells with cytolytic functions in various species, including humans and rodent

More stories on Th17 cells

For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. the Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4(+) T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4(+) T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. the Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-beta or TGF-beta plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.Crohn's and Colitis Foundation of AmericaNIHLa Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USAUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilNIH: RO1 AI050265-06Web of Scienc