Jueves 28 de Febrero de 2008; 09:15 hrs.

 

Multiple Dendritic Cell Populations Activate CD4+ T Cells after Viral Stimulation

 

Mount AM, Smith CM, Kupresanin F, Stoermer K, Heath WR, et al. (2008) Multiple Dendritic Cell Populations Activate CD4+ T Cells after Viral Stimulation. PLoS ONE 3(2): e1691 doi:10.1371/journal.pone.0001691

Dendritic cells (DC) are a heterogeneous cell population that bridge the innate and adaptive immune systems. CD8α DC play a prominent, and sometimes exclusive, role in driving amplification of CD8+ T cells during a viral infection. Whether this reliance on a single subset of DC also applies for CD4+ T cell activation is unknown. We used a direct ex vivo antigen presentation assay to probe the capacity of flow cytometrically purified DC populations to drive amplification of CD4+ and CD8+ T cells following infection with influenza virus by different routes. This study examined the contributions of non-CD8α DC populations in the amplification of CD8+ and CD4+ T cells in cutaneous and systemic influenza viral infections. We confirmed that in vivo, effective immune responses for CD8+ T cells are dominated by presentation of antigen by CD8α DC but can involve non-CD8α DC. In contrast, CD4+ T cell responses relied more heavily on the contributions of dermal DC migrating from peripheral lymphoid tissues following cutaneous infection, and CD4 DC in the spleen after systemic infection. CD4+ T cell priming by DC subsets that is dependent upon the route of administration raises the possibility that vaccination approaches could be tailored to prime helper T cell immunity....Más..

 

Jueves 21 de Febrero de 2008; 12:16hrs.

Toll-like receptors two-edged sword: when immunity meets apoptosis

 

• Bruno Salaun, Pedro Romero, Serge Lebecque. European Journal of Immunology 2007; 37: 3311-3318
  
  
• Toll-like receptors (TLR) have emerged as key players in the detection of pathogens and the induction of anti-microbial immune response. TLR recognize pathogen-associated molecular patterns, and trigger anti-microbial innate immune responses ranging from the secretion of pro-inflammatory mediators to the increase of natural killer cell cytotoxicity. Besides activating the innate immune response, TLR engagement also shapes the adaptive immune response. Indeed, the broad diversity of signaling pathways initiated by TLR is progressively unraveled. Recent reports suggested that among the anti-microbial defenses they initiate, members of the TLR family can induce apoptosis. This review focuses on this newly described function of TLR, and emphasizes the similarities and differences between the different apoptosis-signaling pathways described downstream of TLR. The functional relevance of TLR-triggered apoptosis is also discussed, as therapeutic applications are likely to ensue in the near future.....Más...

 

Miércoles 20 de Febrero de 2008;09:27 hrs.

Antigen presentation by monocytes and monocyte-derived cells

 

• Gwendalyn J Randolpha, Claudia Jakubzicka and Chunfeng Qu. Current Opinion in Immunology
  Volume 20, Issue 1, February 2008, Pages 52-60
  
• Monocytes are circulating mononuclear phagocytes with a fundamental capacity to differentiate into macrophages. This differentiation can, in the presence of the right environmental cues, be re-directed instead to dendritic cells (DCs). Recent advances have been made in understanding the role of monocytes and their derivatives in presenting antigen to drive immune responses, and we review this topic herein. We briefly discuss the heterogeneity of monocytes in the blood and subsequently raise the possibility that one of the major monocyte phenotypes in the blood corresponds with a population of ‘blood DCs’ previously proposed to drive T-independent antibody reactions in the spleen. Then we evaluate the role of monocytes in T-dependent immunity, considering their role in acquiring antigens for presentation before exiting the bloodstream and their ability to differentiate into macrophages versus antigen-presenting DCs. Finally, we review recent literature on the role of monocyte-derived cells in cross-presentation and discuss the possibility that monocyte-derived cells participate critically in processing antigen for cross-priming, even if they do not present that antigen to T cells themselves.....Más...

 

Martes 19 de Febrero de 2008; 22:12 hrs.

Human regulatory T cells inhibit polarization of T helper cells toward antigen-presenting cells via a TGF-β-dependent mechanism

 

• Michael Esquerré, Baptiste Tauzin, Martine Guiraud, Sabina Müller, Abdelhadi Saoudi, and Salvatore Valitutti. Published online on February 11, 2008, 10.1073/pnas.0708350105 PNAS, February 19, 2008 vol. 105 no. 7 2550-2555
  
• The molecular mechanisms used by regulatory T cells (Treg) to inhibit the effector phase of adaptive immune responses are still elusive. In the present work, we investigated the possibility that Treg may interfere with a basic biological function of T helper cells (TH): polarization of secretory machinery for dedicated help delivery. To address this question, we visualized by confocal microscopy different parameters of activation in TH and Treg cells interacting simultaneously with individual antigen-presenting cells (APC). Our results show that, although productive TCR engagement in TH/APC conjugates was unaffected by the presence of adjacent Treg, the reorientation of TH secretory machinery toward APC was strongly inhibited. Blocking TGF-β completely reverted Treg induced inhibition of TH polarization. Our results identify a previously undescribed mechanism by which Treg inhibit effector T cells. TGF-β produced by adjacent Treg interferes with polarization of TH secretory machinery toward APC, thus affecting a crucial step of TH-mediated amplification of the immune response......Más...

 

Martes 19 de Febrero de 2008; 11:10 hrs.

Generation of highly suppressive adaptive CD8+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation

 

• Milada Mahic, Karen Henjum, Sheraz Yaqub, Bjørn Atle Bjørnbeth, Knut Martin Torgersen, Kjetil Taskén, Einar Martin Aandahl European Journal of Immunology 2008; 38:640-646
• Continuous antigen stimulation of CD4+CD25- T cells leads to generation of adaptive CD4+CD25+FOXP3+ regulatory T (TR) cells. Here, we show that highly suppressive adaptive CD8+CD25+FOXP3+ T cells can be generated in the same manner by continuous antigen stimulation in the presence of CD14+ monocytes. During the course of stimulation, acquisition of immunosuppressive properties develops in parallel with up-regulation and expression of cytotoxic molecules. The CD8+ TR cells inhibit CD4+ and CD8+ T cell proliferation and cytokine production, but do not alter the expression of granzyme A and granzyme B or perforin in CD8+ effector T cells. Although, the CD8+ TR cells express prostaglandin E2, IL-10 and TGF-, the mechanism of suppression was independent of these soluble factors. In contrast to adaptive CD4+ TR cells, the CD8+ TR cells suppress mainly by a contact-dependent mechanism as evident from transwell experiments. However, neither blocking antibodies to CTLA-4, CD80 nor CD86 could reverse CD8+ TR-mediated suppression, indicating that other mechanism(s) must be employed by these cells.....Más.

 

Martes 19 de Febrero de 2008; 11:05 hrs.

Accelerating the secondary immune response by inactivating CD4+CD25+ T regulatory cells prior to BCG vaccination does not enhance protection against tuberculosis

 

• Kylie M. Quinn, Fenella J. Rich, Lisa M. Goldsack, Geoffrey W. de Lisle, Bryce M. Buddle, Brett Delahunt, Joanna R. Kirman. European Journal of Immunology 2008; 38:695-705
• CD4+CD25+ natural T regulatory cells (Tregs) have been shown to suppress protective immune responses in several different vaccination models. Since the effect of Tregs on vaccination against tuberculosis (Tb) was unknown, we used a murine model to investigate whether natural Tregs suppress the development of protective immunity following Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination. Using a monoclonal antibody against CD25, natural Tregs were inactivated prior to vaccination with BCG. The primary immune response was evaluated after BCG vaccination and the secondary immune response was assessed after an intranasal BCG challenge 42 days after vaccination. Inactivation of natural Tregs prior to vaccination led to an increased immune response 14 days after vaccination, increased numbers of antigen-responsive lymphocytes immediately prior to secondary challenge and the earlier appearance of IFN--producing CD4+ and CD8+ lymphocytes in the draining lymph nodes and lungs after challenge. Despite this, protection from virulent Mycobacterium tuberculosis or M. bovis aerosol challenge was unaffected by natural Treg inactivation prior to BCG vaccination. This suggests that increasing the primary and accelerating the secondary immune responses by inactivating natural Tregs at the time of vaccination, does not affect the development of protective immunity to Tb.......Más.

 

Lunes 18 de Febrero de 2008; 16:55 hrs.

CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity

 

• Thomas Calzascia, Marc Pellegrini, Albert Lin, Kristine M. Garza, Alisha R. Elford, Arda Shahinian, Pamela S. Ohashi, and Tak W. Mak. Published online on February 14, 2008. Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0712135105
• There are many inhibitory mechanisms that function at the cellular and molecular levels to maintain tolerance. Despite this, self-reactive clones escape regulatory mechanisms and cause autoimmunity in certain circumstances. We hypothesized that the same mechanisms that permit T cells to expand during homeostatic proliferation may inadvertently promote autoimmunity under certain conditions. One major homeostatic cytokine is IL-7, and studies have linked it or its receptor to the development of multiple sclerosis and other autoimmune diseases. We show in a model of β-islet cell self-reactivity that the transfer of activated autoreactive CD4 T cells can prime and expand endogenous autoreactive CD8 T cells in a CD28- and CD40-dependent manner through the licensing of dendritic cells. Despite this, mice do not develop diabetes. However, the provision of exogenous IL-7 or the physiological production of IL-7 associated with lymphopenia was able to profoundly promote the expansion of self-reactive clones even in the presence of regulatory T cells. Autoimmune diabetes rapidly ensued with CD4 help and the subsequent activation of CD8 T cells, which contributed to disease progression. With the advent of many biologicals targeting TNF, IL-6, and IL-1 and their effective use in the treatment of autoimmune diseases, we propose that IL-7 and its receptor may be promising targets for biological agents in the treatment of autoimmunity.....Más.

 

Martes 12 de Febrero de 2008; 10:00 hrs.

The Effect of Trim5 Polymorphisms on the Clinical Course of HIV-1 Infection

 

• van Manen D, Rits MAN, Beugeling C, van Dort K, Schuitemaker H, et al. PLoS Pathogens Vol. 4, No. 2, e18 doi:10.1371/journal.ppat.0040018

• The antiviral factor tripartite interaction motif 5α (Trim5α) restricts a broad range of retroviruses in a species-specific manner. Although human Trim5α is unable to block HIV-1 infection in human cells, a modest inhibition of HIV-1 replication has been reported. Recently two polymorphisms in the Trim5 gene (H43Y and R136Q) were shown to affect the antiviral activity of Trim5α in vitro. In this study, participants of the Amsterdam Cohort studies were screened for polymorphisms at amino acid residue 43 and 136 of the Trim5 gene, and the potential effects of these polymorphisms on the clinical course of HIV-1 infection were analyzed. In agreement with the reported decreased antiviral activity of Trim5α that contains a Y at amino acid residue 43 in vitro, an accelerated disease progression was observed for individuals who were homozygous for the 43Y genotype as compared to individuals who were heterozygous or homozygous for the 43H genotype. A protective effect of the 136Q genotype was observed but only after the emergence of CXCR4-using (X4) HIV-1 variants and....Más.