HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Related articles in The JI Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content

IN THIS ISSUE

Coagulation and inflammation

Mounting evidence demonstrates that an association between the inflammatory and coagulant cascades influences the outcome of patients experiencing sepsis and acute lung injury. The conversion of plasminogen to plasmin is catalyzed by urokinase plasminogen activator (uPA), an enzyme that is constitutively expressed by both macrophages and neutrophils. On p. 5644 , Abraham et al. show that uPA enhanced neutrophil responses to LPS and exacerbated lung injury during endotoxemia. They found that human recombinant uPA increased LPS-induced activation of the Akt and JNK intracellular signaling pathways in murine neutrophils in vitro. Similarly, uPA increased the expression of the proinflammatory cytokines IL-1, MIP-2, and TNF- and nuclear translocation of the transcription factor NF-B in neutrophils activated by submaximal doses of LPS. Of particular interest, uPA^-/- mice were protected from endotoxemia-induced lung injury, suggesting that uPA plays a major role in inflammatory responses in vivo.

Making memories

When an animal is infected with respiratory virus, CD8⁺ T cells proliferate and differentiate to become effector cells, which function in clearance of the virus. After the infection is resolved, many effector cells are eliminated; however, virus-specific CD8⁺ memory T cells persist in both lymphoid and nonlymphoid tissues. CD8⁺ memory T cells in lymphoid tissue show phenotypic and functional characteristics that differ from those of peripheral memory cells. Neither the relationship between lymphoid and peripheral memory cells, nor the process by which they arise, is well understood. Cauley et al. (p. 5597 ) examined the development of virus-specific lymphoid and peripheral CD8⁺ memory T cells in mice during primary and secondary respiratory virus infection. They found no detectable differences in the proliferation kinetics during acute viral infection of CD8⁺ memory T cells in broncho-alveolar lavage, lung parenchyma, mediastinal lymph node, or spleen. Additionally, virus-specific CD8⁺ memory T cells appeared to be generated throughout the response to the infection. Following secondary infection with the same virus, peripheral and lymphoid CD8⁺ memory T cells underwent proliferation and renewal in both Ab-deficient and Ab-sufficient mice. However, the recruitment of CD8⁺ memory T cells to lung airways during a secondary infection was delayed in mice with virus-specific Abs, suggesting that the inflammatory response may differ in primary and secondary infections. These studies provide further insight into the development and renewal of CD8⁺ memory T cells in peripheral and lymphoid tissues following infection.

Roles for regulatory T cells

Regulatory T cells suppress Ag-induced activation of T cells in vitro and in vivo. This suppression is a complex process, and the mechanisms involved remain unclear. Two papers in this issue examine the roles of CD25⁺CD4⁺ regulatory T cells in different disease processes. In the first, Hadeiba and Locksley (p. 5502 ) investigated the role of CD25⁺CD4⁺ regulatory T cells in asthma pathogenesis using a murine model of chronic airway allergen exposure. The authors generated transgenic mice that express the model Ag, OVA, under control of the surfactant C promoter and crossed these mice onto an OVA-specific TCR background to overcome tolerance. They found that CD4⁺ T cells infiltrated the lungs of the double transgenics, associated with areas of mucin-containing goblet cell hyperplasia. However, the authors observed that type 2 effector function of infiltrating CD4⁺ T cells was inhibited by CD25⁺CD4⁺ regulatory T cells that accumulated in the lungs, although these regulatory T cells were unable to prevent the development of acute airway hyperreactivity after Ag challenge. In the second paper, Vasu et al. (p. 5511 ) examined the effect of different dendritic cell (DC) subsets on the development of experimental autoimmune thyroiditis in CBA/J mice. The authors used Flt3-ligand or GM-CSF to differentially activate different DC subtypes, leading to either a type 1 or type 2 response, respectively. Treatment with Flt3-ligand exacerbated disease, whereas treatment with GM-CSF prevented or suppressed disease development. GM-CSF treated mice showed an increased proportion of CD4⁺CD25⁺ regulatory T cells in spleen relative to thyroglobulin immunized controls and these cells suppressed anti-thyroglobulin specific CD4⁺ T cell proliferation. Hence, in both these disease models, CD4⁺CD25⁺ regulatory T cells suppress the activity or proliferation of type 2 CD4⁺ effector cells.

CD1 Ag presentation

Human group 1 CD1 proteins (Cd1a, CD1b, CD1c) monitor endosomal compartments for phagocytosed microbial lipid and glycolipid Ags, binding to and presenting these Ags to T cells. Dendritic cells (DCs) in both lymphoid and nonlymphoid tissues express CD1 in humans; DCs also phagocytose organisms such as Mycobacterium tuberculosis. Since CD8⁺ T cells are involved in host defense against Mycobacterium tuberculosis, Kawashima et al. (p. 5345 ) examined the CD8⁺ T cell response in individuals immunized with Mycobacterium bovis bacillus Calmette-Guérin (BCG). They found that CD8⁺ T cells from peripheral blood recognized autologous BCG-infected DCs in a CD1-dependent, MHC-independent manner. Detection of CD1-reactive CD8⁺ T cells required the use of live bacteria to infect DCs (no CD8⁺ T cell activation was observed using dead bacteria). Macrophages, which like DCs phagocytose mycobacteria and participate in Ag presentation, but which lack expression of group 1 CD1 molecules, were unable to activate BCG-specific CD8⁺ T cells. Abs to CD1a, CD1b and CD1c molecules, but not to MHC class I or II molecules, inhibited the CD8⁺ T cell response to varying extents in all 11 subjects tested. These studies raise the possibility that the CD8⁺ T cell response to BCG is predominantly directed against CD1-presented lipid Ags, thereby impacting approaches to tuberculosis vaccine development.

Is it bound?

A number of growth factors and cytokines bind to various components of the extracellular matrix. IL-2, an important regulator of T cell homeostasis, is known to bind to heparin sulfate found both in the extracellular matrix and on cell surfaces. On p. 5470 , Wrenshall et al. show that T cell responses to IL-2 in vivo are mediated by heparin sulfate-bound IL-2, but not by soluble IL-2. The authors show that spleens of unmanipulated mice contain constitutive levels of IL-2 that colocalizes with heparin-sulfate. When TCR transgenic CD4⁺ T cells from IL-2^+/+ or IL-2^-/- mice were transferred into IL-2^+/+ recipients, these cells proliferated more rapidly than either IL-2^+/+ or IL-2^-/- cells transferred into IL-2^-/- mice. The proliferation in IL-2^+/+ recipients was followed by a rapid decrease in T cell number that did not occur in IL-2^-/- recipients. The authors then used a mutant IL-2 containing a single amino acid substitution that prevents it binding to heparin sulfate but not does diminish its bioactivity in vitro. TCR transgenic IL-2^-/- T cells proliferated when transferred into mice that lacked IL-2 but had been reconstituted by infusion of wild-type IL-2. However, they did not proliferate when transferred into mice reconstituted with the mutant IL-2 that is unable to bind heparin sulfate. The authors propose that host-derived, tissue-bound IL-2 facilitates both T cell activation and the subsequent death of activated T cells and suggest that tumors or viruses might evade immune responses by modifying heparin sulfate and its ability to bind IL-2.

Signaling for homeostasis

Careful regulation of T cell homeostasis is critical to permit normal immune responses and prevent undesirable self-targeted responses. This regulation is largely controlled by cytokines, including IL-2 and TGF-. IL-2 exerts a proliferative signal on T cells, whereas TGF- acts as an inhibitor of proliferation. TGF-R signaling activates the Smad family of signal transducers while IL-2R signaling occurs through both the Shc and STAT5 pathways. Using the IL-2-dependent CD8⁺ T cell line CTLL-2, Nelson et al. (p. 5563 ) investigated the molecular mechanism by which TGF- inhibits IL-2 driven proliferation. They found that TGF- inhibited the ability of IL-2 to induce expression of target genes through the Shc and STAT5 pathways. This inhibition of IL-2 target gene induction, as well as T cell proliferation, was abrogated in cells transfected with a dominant negative form of Smad3. TGF- exerted its inhibitory effect through both the Shc and STAT5 pathways, but did not inhibit proximal signaling events in either pathway. Rather, TGF- selectively inhibited the IL-2-mediated induction of genes involved in proliferation, but not those involved in cell survival, downstream of either pathway. The sensitivity of IL-2 target genes to TGF- was governed by regulatory elements in promoter/enhancer regions of the target genes themselves. TGF- therefore induces Smad3 to modify IL-2-dependent gene expression patterns, uncoupling the proliferative and anti-apoptotic effects of IL-2.

Cutaneous cytokines

Interleukin-23 is a type-1 cytokine composed of a p19 subunit and the p40 subunit found in IL-12. IL-23 binds to IL-12R1, but not IL-12R2, and like IL-12, is mainly produced by activated dendritic cells. Unlike IL-12, IL-23 strongly augments the proliferation of mouse CD4⁺CD45Rb^low memory T cells. To study the role of IL-23 in the skin, Kopp et al. (p. 5438 ) used transgenic mice expressing the p40 subunit of IL-12/IL-23 under the control of the keratin-14 promoter, thereby targeting expression of the transgene to the basal layer of the epidermis. These mice manifest an inflammatory skin disease similar to human eczema. The authors demonstrated constitutive production of IL-23, but not IL-12, in the basal keratinocytes. They show that p19 mRNA is present in basal keratinocytes from both the transgenic mice and littermate controls, but that littermate controls do not express p40 in basal keratinocytes and, therefore, do not produce IL-23. Injection of recombinant IL-23 into littermate mice resulted in the type of skin inflammation seen in the transgenic mice. Compared with littermate controls, the p40 transgenic mice show increased numbers of Langerhans cells with a more mature phenotype, correlating with an accelerated rejection of allogeneic skin transplants from transgenic mice compared with their littermates. These studies augment the proinflammatory functions documented to date for IL-23 in vivo and suggest that it may be important in cutaneous immune responses.

Summaries written by Kaylene J. Kenyon, Ph.D.

Related articles in The JI:

Cutting Edge: Major CD8 T Cell Response to Live Bacillus Calmette-Guérin Is Mediated by CD1 Molecules

Tetsuo Kawashima, Yoshihiko Norose, Yoshiyuki Watanabe, Yutaka Enomoto, Hidehiko Narazaki, Eiji Watari, Shigeo Tanaka, Hidemi Takahashi, Ikuya Yano, Michael B. Brenner, and Masahiko Sugita
The JI 2003 170: 5345-5348. [Abstract] [Full Text]  

IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

Tamara Kopp, Petra Lenz, Concha Bello-Fernandez, Robert A. Kastelein, Thomas S. Kupper, and Georg Stingl
The JI 2003 170: 5438-5444. [Abstract] [Full Text]  

Propagation and Control of T Cell Responses by Heparan Sulfate-Bound IL-2

Lucile E. Wrenshall, Jeffrey L. Platt, Elliot T. Stevens, Thomas N. Wight, and John D. Miller
The JI 2003 170: 5470-5474. [Abstract] [Full Text]  

Lung CD25 CD4 Regulatory T Cells Suppress Type 2 Immune Responses But Not Bronchial Hyperreactivity

Husein Hadeiba and Richard M. Locksley
The JI 2003 170: 5502-5510. [Abstract] [Full Text]  

Selective Induction of Dendritic Cells Using Granulocyte Macrophage-Colony Stimulating Factor, But Not fms-Like Tyrosine Kinase Receptor 3-Ligand, Activates Thyroglobulin-Specific CD4⁺/CD25⁺ T Cells and Suppresses Experimental Autoimmune Thyroiditis

Chenthamarakshan Vasu, Rukiye-Nazan E. Dogan, Mark J. Holterman, and Bellur S. Prabhakar
The JI 2003 170: 5511-5522. [Abstract] [Full Text]  

Uncoupling of Promitogenic and Antiapoptotic Functions of IL-2 by Smad-Dependent TGF- Signaling

Brad H. Nelson, Timothy P. Martyak, Lucas J. Thompson, James J. Moon, and Tongwen Wang
The JI 2003 170: 5563-5570. [Abstract] [Full Text]  

Renewal of Peripheral CD8⁺ Memory T Cells During Secondary Viral Infection of Antibody-Sufficient Mice

Linda S. Cauley, Tres Cookenham, Robert J. Hogan, Sherry R. Crowe, and David L. Woodland
The JI 2003 170: 5597-5606. [Abstract] [Full Text]  

Urokinase-Type Plasminogen Activator Potentiates Lipopolysaccharide-Induced Neutrophil Activation

Edward Abraham, Margaret R. Gyetko, Katherine Kuhn, John Arcaroli, Derek Strassheim, Jong Sung Park, Sreerama Shetty, and Steven Idell
The JI 2003 170: 5644-5651. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Related articles in The JI Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content