Under normal circumstances, the respiratory tract maintains immune tolerance in the face of constant antigen provocation. Using a murine model of tolerance induced by repeated exposure to a low dose of aerosolized antigen, we show an important contribution by CD4+ T cells in the establishment and maintenance of tolerance. The CD4+ T cells expressed both cell surface and soluble TGF-β and inhibited the development of an allergic phenotype when adoptively transferred to naive recipient mice. While cells expressing cell surface TGF-β were detectable in mice with inflammation, albeit at a lower frequency compared with that in tolerized mice, only those from tolerized mice expressed FOXP3. Blockade of TGF-β in vitro and in vivo interfered with immunosuppression. Although cells that expressed TGF-β on the cell surface (TGF-β+), as well as the ones that did not (TGF-β–), secreted equivalent levels of soluble TGF-β, only the former were able to blunt the development of an allergic phenotype in mice. Strikingly, separation of the TGF-β+ cells from the rest of the cells allowed the TGF-β– cells to proliferate in response to antigen. We propose a model of antigen-induced tolerance that involves cell-cell contact with regulatory CD4+ T cells that coexpress membrane-bound TGF-β and FOXP3.
Marina Ostroukhova, Carole Seguin-Devaux, Timothy B. Oriss, Barbara Dixon-McCarthy, Liyan Yang, Bill T. Ameredes, Timothy E. Corcoran, Anuradha Ray
We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-α and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction.
Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher
Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1β, IL-6, and TNF-α. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.
Vishwa Deep Dixit, Eric M. Schaffer, Robert S. Pyle, Gary D. Collins, Senthil K. Sakthivel, Ravichandran Palaniappan, James W. Lillard Jr., Dennis D. Taub
Daniele Accapezzato, Vittorio Francavilla, Marino Paroli, Marco Casciaro, Lucia Valeria Chircu, Agostino Cividini, Sergio Abrignani, Mario U. Mondelli, Vincenzo Barnaba
The progeny of T lymphocytes responding to immunization mostly die rapidly, leaving a few long-lived survivors functioning as immune memory. Thus, control of this choice of death versus survival is critical for immune memory. There are indications that reactive radicals may be involved in this death pathway. We now show that, in mice lacking inducible nitric oxide synthase (iNOS), higher frequencies of both CD4 and CD8 memory T cells persist in response to immunization, even when iNOS+/+ APCs are used for immunization. Postactivation T cell death by neglect is reduced in iNOS–/– T cells, and levels of the antiapoptotic proteins Bcl-2 and Bcl-xL are increased. Inhibitors of the iNOS-peroxynitrite pathway also enhance memory responses and block postactivation death by neglect in both mouse and human T cells. However, early primary immune responses are not enhanced, which suggests that altered survival, rather than enhanced activation, is responsible for the persistent immunity observed. Thus, in primary immune responses, iNOS in activated T cells autocrinely controls their susceptibility to death by neglect to determine the level of persisting CD4 and CD8 T cell memory, and modulation of this pathway can enhance the persistence of immune memory in response to vaccination.
Monika Vig, Smita Srivastava, Usha Kandpal, Hadassah Sade, Virginia Lewis, Apurva Sarin, Anna George, Vineeta Bal, Jeannine M. Durdik, Satyajit Rath
T cell reactivity to minor histocompatibility (mH) antigens is responsible for rejection of HLA-matched allografts, limiting the effectiveness of transplantation for the treatment of end-stage organ failure. The deadbox gene Dby is located on the Y chromosome and encodes an mH antigen that prompts rejection of male tissues by female mice. Establishing a network of regulatory T (Treg) cells that is capable of coercing naive cells to adopt a tolerant phenotype offers an attractive strategy for immune intervention in such deleterious immune responses. While various approaches have successfully induced a dominant form of transplantation tolerance, they share the propensity to provoke chronic, incomplete activation of T cells. By identifying the T cell receptor (TCR) contact sites of the dominant epitope of the Dby gene product, we have designed an altered peptide ligand (APL) that delivers incomplete signals to naive T cells from A1 ∞ RAG1–/– mice that are transgenic for a complementary TCR. Administration of this APL to female transgenic mice polarizes T cells toward a regulatory phenotype, securing a form of dominant tolerance to male skin grafts that is capable of resisting rejection by naive lymphocytes. Our results demonstrate that incomplete signaling through the TCR may establish a network of Treg cells that may be harnessed in the service of transplantation tolerance.
Tse-Ching Chen, Herman Waldmann, Paul J. Fairchild
Administration of an agonistic anti-CD28 mAb paradoxically inhibits donor T cell expansion and prevents graft-versus-host disease (GVHD) in mice. Here we examined the mechanism of anti-CD28–mediated immunosuppression and found that anti-CD28 mAb activated, rather than blocked, CD28-mediated signaling in vivo. Anti-CD28 treatment prevented GVHD by selectively depleting alloantigen-activated donor T cells through apoptosis but spared the T cells that did not recognize recipient alloantigens. Overexpression of Bcl-xL did not protect T cells from depletion and did not affect GVHD prevention after anti-CD28 treatment. Depletion of activated T cells mediated through CD28 did not depend on the expression of death receptors Fas and TNF receptors type I and II, but both the depletion of activated T cells and the suppressive effect of anti-CD28 mAb on GVHD lethality required donor-derived IFN-γ production. This study demonstrates that agonistic Ab’s specific for the CD28 costimulatory molecule may be used as novel therapeutic agents to abrogate pathogenic T cell responses by selective depletion of activated T cells.
Xue-Zhong Yu, Michael H. Albert, Paul J. Martin, Claudio Anasetti
OCH, a sphingosine-truncated analog of α-galactosylceramide (αGC), is a potential therapeutic reagent for a variety of Th1-mediated autoimmune diseases through its selective induction of Th2 cytokines from natural killer T (NKT) cells. We demonstrate here that the NKT cell production of IFN-γ is more susceptible to the sphingosine length of glycolipid ligand than that of IL-4 and that the length of the sphingosine chain determines the duration of NKT cell stimulation by CD1d-associated glycolipids. Furthermore, IFN-γ production by NKT cells requires longer T cell receptor stimulation than is required for IL-4 production by NKT cells stimulated either with immobilized mAb to CD3 or with immobilized “αGC-loaded” CD1d molecules. Interestingly, transcription of IFN-γ but not that of IL-4 was sensitive to cycloheximide treatment, indicating the intrinsic involvement of de novo protein synthesis for IFN-γ production by NKT cells. Finally, we determined c-Rel was preferentially transcribed in αGC-stimulated but not in OCH-stimulated NKT cells and was essential for IFN-γ production by activated NKT cells. Given the dominant immune regulation by the remarkable cytokine production of ligand-stimulated NKT cells in vivo, in comparison with that of (antigen-specific) T cells or NK cells, the current study confirms OCH as a likely therapeutic reagent for use against Th1-mediated autoimmune diseases and provides a novel clue for the design of drugs targeting NKT cells.
Shinji Oki, Asako Chiba, Takashi Yamamura, Sachiko Miyake
While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation.
Birgit Liliensiek, Markus A. Weigand, Angelika Bierhaus, Werner Nicklas, Michael Kasper, Stefan Hofer, Jens Plachky, Herman-Josef Gröne, Florian C. Kurschus, Ann Marie Schmidt, Shi Du Yan, Eike Martin, Erwin Schleicher, David M. Stern, Günter J. Hämmerling, Peter P. Nawroth, Bernd Arnold
Toll-like receptors (TLRs) mediate host responses to bacterial gene products. As the airway epithelium is potentially exposed to many diverse inhaled bacteria, TLRs involved in defense of the airways must be broadly responsive, available at the exposed apical surface of the cells, and highly regulated to prevent activation following trivial encounters with bacteria. We demonstrate that TLR2 is enriched in caveolin-1–associated lipid raft microdomains presented on the apical surface of airway epithelial cells after bacterial infection. These receptor complexes include myeloid differentiation protein (MyD88), interleukin-1 receptor–activated kinase-1, and TNF receptor–associated factor 6. The signaling capabilities of TLR2 are amplified through its association with the asialoganglioside gangliotetraosylceramide (Galβ1,2GalNAcβ1,4Galβ1,4Glcβ1,1Cer), which has receptor function itself for many pulmonary pathogens. Ligation of either TLR2 or asialoGM1 by ligands with specificity for either receptor, by Pseudomonas aeruginosa, or by Staphylococcus aureus stimulates IL-8 production through activation of NF-κB, as mediated by TLR2 and MyD88. Thus, TLR2 in association with asialo-glycolipids presented within the context of lipid rafts provides a broadly responsive signaling complex at the apical surfaces of airway cells to initiate the host response to potential bacterial infection.
Grace Soong, Bharat Reddy, Sach Sokol, Robert Adamo, Alice Prince