Jun 1, 2006 - shown, however, that TOR participation is stimulus and/or cell-type specific.1 This may indicate that TOR is involved in B-cell metab- olism in ...
shown, however, that TOR participation is stimulus and/or cell-type specific.1 This may indicate that TOR is involved in B-cell metabolism in the presence of other stimulatory signals to be determined. These new results should open the way to new studies on B-cell metabolism to determine how glucose utilization is altered not only by other stimulatory conditions, but also in the progression of B cells through peripheral development. The various B-cell subsets that have been described from transitional cells to plasma cells have very different functions in
health and in disease and, one might speculate, different energy needs. A better understanding of these energy requirements and their regulation may allow targeting of specific Bcell subsets for amplification or reduction, according to therapeutic requirements. ■
REFERENCES 1. Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nature Rev Immunol. 2005;5:844-852. 2. Ravetch JV, Bolland S. IgG Fc receptors. Ann Rev Immunol. 2001;19:275-290.
● ● ● HEMOSTASIS
Comment on Chen et al, page 4364
Matrix rules: microfibrillar protein controls vascular development ---------------------------------------------------------------------------------------------------------------Tatiana V. Byzova
CLEVELAND CLINIC FOUNDATION
In this issue, Chen and colleagues describe how a component of the extracellular matrix, microfibril-associated glycoprotein-1 (MAGP-1), plays a critical role in the vascular development of zebrafish by regulating blood vessel wall integrity and function via control of integrin-mediated cell-matrix interactions.
R
ecent advances in biomedical research, including the completion of genome sequencing, emphasize the need for functional
analyses of genes regulating essential physiologic and pathologic processes. The zebrafish offers numerous advantages as a genetic model for in-depth studies of various aspects of development, including the formation of the cardiovascular system. Chen and colleagues developed a morpholino antisense oligonucleotide (MO)– based functional screen in zebrafish to identify previously unrecognized regulators of cardiovascular development. Using this approach, the group previously reported that syndecan-2, a cell-surface heparan sulfate Chen and colleagues demonstrated that MAGP-1, which is functionally associated proteoglycan, is an eswith a major component of microfibrils, fibrillin-1, is recognized by integrins on the sential player in the cell surface as controlling microfibril structure and tissue integrity. MAGP-1 was process of angiogenesis identified as a key regulator of vasculature development in zebrafish, and its in zebrafish.1 knockdown results in the formation of dilated blood vessels with irregular lumens. 4202
In this issue, Chen and colleagues present a comprehensive in vivo study demonstrating that MAGP-1, a component of fibrillin-rich microfibrils, plays an essential role in vascular morphogenesis in zebrafish. Microfibrils are important structural components of most connective tissues, including, but not limited to, blood vessels, lungs, and elastic ligaments (reviewed in Kielty et al2). The importance of microfibrils is underscored by the consequences of mutations in fibrillin-1 linked to the heritable disorder Marfan syndrome. For the first time, direct in vivo evidence linking microfibrillar protein MAGP-1 to vascular development and function is presented. Both underexpression and overexpression of MAGP-1 cause defects in vasculature, emphasizing the need for tight regulation of this protein during development. Knockdown of MAGP-1 results in the formation of a dilated caudal vein as well as blood vessels in the brain and eyes and irregular lumens of axial vessels (see figure). Reduced caudal-vein branching in MAGP-1 morphants suggests a critical role for MAGP-1 in vascular patterning. In situ hybridization studies combined with results of expression of an MAGP-1–monomeric RFP fusion construct revealed that MAGP-1 is expressed in regions of elastic-fiber formation and localized in areas where vascular dilation was observed in MAGP-1 morphants. Chen and colleagues have shown that MAGP-1 morphants are characterized by the fragmented elastic fibers around dilated vessels. Furthermore, histologic analysis revealed the detachment and overall loose association of cells with the extracellular matrix in MAGP-1 morphants, indicating that MAGP-1 is required for maintaining the proper architecture of the blood vessel wall. Next, a synergism between subthreshold doses of MAGP-1 MO and an integrin antagonist resulting in blood vessel dilation was observed. This approach has proved very efficient in the identification of the functional relationships in vivo (which is one of the most difficult tasks in experimental biology).3 Thus, it appears that in vivo interaction between integrins and MAGP-1 might be involved in the regulation of vascular development. Of interest, MAGP-1 does not have an “RGD” motif within its sequence, in contrast to its closest relative, MAGP-2, which was previously identified as an integrin ligand.4 Furthermore, functional in vivo interaction between 1 JUNE 2006 I VOLUME 107, NUMBER 11
blood
MAGP-1 and fibrillin-1 (both proteins are components of microfibrils) during vascular development was established. Thus, the study by Chen et al not only identifies MAGP-1 as a new regulator of elastic-fiber architecture, vasculature development, and function, but it also determines the functional partners for MAGP-1. These findings open avenues for further research and new clinical applications in cardiovascular disease. ■
REFERENCES 1. Chen E, Hermanson S, Ekker SC. Syndecan-2 is essential for angiogenic sprouting during zebrafish development. Blood. 2004;103:1710-1719. 2. Kielty CM, Sherratt MJ, Marson A, Baldock C. Fibrillin microfibrils. Adv Protein Chem. 2005;70:405-436. 3. Feldner J, Becker T, Goishi K, et al. Neuropilin-1a is involved in trunk motor axon outgrowth in embryonic zebrafish. Dev Dyn. 2005;234:535-549. 4. Gibson MA, Leavesley DI, Ashman LK. Microfibrilassociated glycoprotein-2 specifically interacts with a range of bovine and human cell types via alphaVbeta3 integrin. J Biol Chem. 1999;274:13060-13065.
● ● ● IMMUNOBIOLOGY
Comment on Noble et al, page 4475
A tale of two T cells: suppressor CD8 T---------------------------------------------------------------------------------------------------------------cells recalled to life Edmund K. Waller
WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
The paper by Noble and colleagues describes a novel population of regulatory CD8! T cells that is generated in vitro by exposure of CD8! T cells to the combination of IL-4 and IL-12.
I
n the 1970s, 2 types of CD8! T cells were described: cytotoxic and suppressor, with the suppressor population found in the blood of patients who underwent allogeneic bone marrow transplantation (BMT) and Hodgkin lymphoma patients treated with total lymphoid irradiation.1,2 Suppressor T cells inhibited lectin-induced T-cell proliferation and B-cell immunoglobulin synthesis and T-cell proliferation in mixed lymphocyte reactions.3 Suppressor T cells were hypothesized to be responsible for the clinical immunosuppression observed among these patients,4 but their precise identity, distinction from effector CD8! T cells, and mechanism of action were unclear. Interest in suppressor CD8! T cells waned during the decades in which antigenspecific cytotoxic CD8! T-cell responses were defined and antigen presentation by dendritic cells was discovered. Data presented by Noble and colleagues in this issue of Blood shed new light on these interesting regulatory cells. The authors found that CD8! Tregs inhibited the generation of Th1/Tc1 and Th2/Tc1 antigen-specific effector responses. The cytokine profile of the CD8! Tregs was similar to that of their CD4! counterparts, with synthesis and secretion of high levels of IL-10 and IFN-", but the former cells are augmented by the presence of
blood 1 J U N E 2 0 0 6 I V O L U M E 1 0 7 , N U M B E R 1 1
glucocorticoids, while CD4! Tregs were not. The presence of a phenotypically similar population following in vivo immunization
suggests that this phenomenon is part of the physiologic regulation of immune responses. The data presented by the authors use OT-1 and OT-2 transgenic T cells to track antigenspecific immune responses in vivo as well as a parenteral 3 F1 graft-versus-host disease (GVHD) model to demonstrate physiologic relevance of the CD8 Tregs to regulating immune responses. Inhibition of antigen-specific effector immune responses required relatively high ratios of CD8! Tregs to effectors with cell-to-cell contact, and was not blocked by neutralizing secreted IL-10 or TGF-#, or the presence of a Golgi poison to block cytokine secretion, but could be reversed by anti-CD28 antibodies. These new data indicate that the regulation of immune responses is redundant, with multiple stimulatory and inhibitory pathways that converge on the same intermediates and effector cell populations. The addition of CD8! Tregs to the regulatory dendritic cells that are generated by TGF-#, IL-10, or VIP5 adds another important counterregulatory system that limits immune responses. The map of these connections begins to look like a New York City subway map, with overlapping routes delivering counterbalancing activation and inhibitory signals (see figure).
Pathways of immune regulation. Positive signals for immune activation are shown as green arrows; inhibitory signals are shown as red lines terminating in red bars. Blue arrows represent differentiation pathways and/or secreted cytokines. Generation of CD8! Tregs occurs under the influence of IL-12 made by Th1 and IL-4 made by Th2 T cells. 4203
