RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb–PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2–deficient mice showed that PD-L2 expression on non–T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events

PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1−/− antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1–coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1−/−PD-L2−/− Rag−/− recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity

Educomunicação, Transformação Social e Desenvolvimento Sustentável

Esta publicação apresenta os principais trabalhos dos GTs do II Congresso Internacional de Comunicação e Educação nos temas Transformação social, com os artigos que abordam principalmente Educomunicação e/ou Mídia-Educação, no contexto de políticas de diversidade, inclusão e equidade; e, em Desenvolvimento Sustentável os artigos que abordam os avanços da relação comunicação/educação no contexto da educação ambiental e desenvolvimento sustentável

1 5 2 VOLUME 14 NUMBER 2 FEBRUARY 2013 nature immunology

A r t i c l e s Follicular helper T cells (T FH cells) are a subset of CD4 + T cells that are essential for helping cognate B cells form and maintain the germinal center (GC) reaction and for the development of humoral immune responses. These cells are universally defined by expression of the chemokine receptor CXCR5, which directs them to B cell follicles via gradients of the chemokine CXCL13 (ref. 1). T FH cells also express the transcription factor Bcl-6 and have high expression of the costimulatory receptor ICOS. Both Bcl-6 and ICOS are critical for the differentiation and maintenance of T FH cells 1−4 . In addition, T FH cells secrete large amounts of interleukin 21 (IL-21), which aids in the formation of GCs, isotype switching and the formation of plasma cells 5 . In humans and mice, functionally similar T FH cells can be found in secondary lymphoid organs. CXCR5 + T FH cells are also present in peripheral blood and are found in greater abundance in people with autoantibodies, including patients with systemic lupus erythematosus, myasthenia gravis or juvenile dermatomyositis. However, the function of circulating T FH cells has remained unclear T FH cells also have high expression of the inhibitory receptor PD-1 (CD279). Signaling through PD-1 attenuates signaling from the T cell antigen receptor (TCR) and inhibits the population expansion, cytokine production and cytolytic function of T cells. In addition, PD-1 promotes the development of induced regulatory T cells (T reg cells) from naive lymphocytes 10-14 . PD-1 has two ligands: PD-L1 (B7-H1) and PD-L2 (B7-DC). PD-L1 has wider expression than does PD-L2, but both PD-L1 and PD-L2 can be expressed on GC B cells and dendritic cells PD-1 also is found on the CD4 + CXCR5 + subset of cells called 'follicular regulatory T cells' (T FR cells), which express the transcription factors Foxp3, Bcl-6 and Blimp-1 and function to inhibit the GC response Here we found that PD-1-PD-L1 interactions inhibited the number of T FR cells, but not of T FH cells, in the lymph nodes. PD-1-deficient mice had more T FR cells in the lymph nodes than did wild-type mice. PD-1-deficient T FR cells in the lymph nodes had an enhanced ability to suppress both the activation of naive T cells and antibody production in vitro. In addition, we found that T FR cells were present in the peripheral blood of mice and that these circulating cells potently regulated humoral immune responses in vivo. Through the use of transfer approaches, we found that T FH cells in the blood promoted antibody production, whereas T FR cells in the blood strongly inhibited antibody production in vivo. We further found that the PD-1 pathway inhibited the function of T FR cells in the blood and that PD-1-deficient T FR cells in the blood had enhanced suppressive ability in vivo. Together our studies identify a previously unknown immunoregulatory role for the PD-1-PD-L1 pathway in limiting th

A marketing plan for California Pizza Kitchen Philippines

California Pizza Kitchen sets to position itself as the leading casual dining restaurant in the premium pizza market that operates as a family-friendly restaurant and offers innovative and high quality pizzas, salads, pastas, and other related products. More so, it intends to provide outstanding quality of customer service and establish a high level of customer loyalty and brand awareness. California Pizza Kitchen sees more expansion by establishing new CPK outlets and/or CPK ASAP in new wave cities and existing market

The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment

The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted