20 research outputs found
Recommended from our members
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
Recommended from our members
CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells
CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker. Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1331-4) contains supplementary material, which is available to authorized users
TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine and Mediate Uptake of Apoptotic Cells
SummaryThe T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Here we showed that TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4+ peritoneal macrophages, TIM-1+ kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. Mutations in the unique cavity of TIM-4 eliminated PS binding and phagocytosis. TIM-4 mAbs that blocked PS binding and phagocytosis mapped to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors whose recognition of PS is critical for the efficient clearance of apoptotic cells and prevention of autoimmunity
Eficacia de la polÃtica monetaria: un análisis conceptual y matemático basado en el modelo IS-LM
CD160 is a cell surface molecule expressed by most NK cells and approximately 50% of CD8(+) cytotoxic T lymphocytes. Engagement of CD160 by MHC class-I directly triggers a costimulatory signal to TCR-induced proliferation, cytokine production and cytotoxic effector functions. The role of CD160 in alloimmunity is unknown. Using a newly generated CD160 fusion protein (CD160Ig) we examined the role of the novel costimulatory molecule CD160 in mediating CD4(+) or CD8(+) T cell driven allograft rejection. CD160Ig inhibits alloreactive CD8(+) T cell proliferation and IFN-γ production in vitro, in particular in the absence of CD28 costimulation. Consequently CD160Ig prolongs fully mismatched cardiac allograft survival in CD4(-/-), CD28(-/-) knockout and CTLA4Ig treated WT recipients, but not in WT or CD8(-/-) knockout recipients. The prolonged cardiac allograft survival is associated with reduced alloreactive CD8(+) T cell proliferation, effector/memory responses and alloreactive IFN-γ production. Thus, CD160 signaling is particularly important in CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo and therefore may serve as a novel target for prevention of allograft rejection
CD160Ig decreases in vivo proliferation of CD28 deficient CD8<sup>+</sup> T cells.
<p>CFSE-labeled splenocytes from C57BL/6 WT, CD8<sup>−/−</sup>, CD4<sup>−/−</sup> or CD28<sup>−/−</sup> mice (6−8×10<sup>7</sup>) were injected into irradiated BALB/c hosts and treated with CD160Ig or control Ig. The precursor division frequency of CD4<sup>+</sup> and CD8<sup>+</sup> T cell subsets in the host spleen was analyzed 3 days later by FACS and calculated as described in Materials and Methods. Representative histograms from one of 3 experiments are shown.</p
CD160 is expressed on CD8 and CD4 T cells.
<p>Naïve or stimulated (ConA) splenocytes from wildtype C57BL/6 (WT), CD4<sup>−/−</sup>, CD8<sup>−/−</sup> and CD28<sup>−/−</sup> mice were stained with anti-CD160. Mean fluorescence intensity of CD160 on naïve CD8<sup>+</sup> and CD4<sup>+</sup> T cells or CD8<sup>+</sup> and CD4<sup>+</sup> T cells expressing an effector/memory phenotype (CD44<sup>high</sup>CD62L<sup>low</sup>) was analyzed. <b>Upper Panel</b>: Representative dot plots of CD160 expressing cells (shaded histograms) in WT mice. <b>Lower Panel</b>: The histograms demonstrate the MFI of CD160<sup>+</sup> cells of the overall CD4<sup>+</sup> or CD8<sup>+</sup> T cell population as the mean ± SEM of 3–5 independent experiments.</p
CD160Ig reduces effector/memory cell generation in CD28<sup>−/−</sup> mice.
<p>Splenocytes from C57BL/6 WT, C57BL/6 WT treated with CTLA4Ig or CD28<sup>−/−</sup> recipients of BALB/c hearts were harvested and CD4<sup>+</sup> or CD8<sup>+</sup> T cells were stained for the effector/memory phenotype, characterized as CD44<sup>high</sup>CD62L<sup>low</sup>. <b>Left Panel:</b> Representative dot plots of CD8<sup>+</sup>CD44<sup>high</sup>CD62L<sup>low</sup> cells. <b>Right Panel:</b> The histograms demonstrate the frequency of CD44<sup>high</sup>CD62L<sup>low</sup> cells as a percentage of the overall CD4<sup>+</sup> or CD8<sup>+</sup> T cell population as the mean ± SEM of 3–5 independent experiments.</p
CD160Ig prolongs fully mismatched heart allograft survival in CD28<sup>−/−</sup> and CD4<sup>−/−</sup>mice.
<p>A) C57BL/6 WT (n = 10); B) CD4<sup>−/−</sup>, (n = 10); C) CD8<sup>−/−</sup> (n = 10); D) CD28<sup>−/−</sup> (n = 10) or E) C57BL/6 WT treated with CTLA4-Ig (n = 5) received Balb/c heart grafts and were treated with CD160Ig (⧫; n = 5) or control Ig (⧫; n = 5); F) C57BL/6 WT (n = 5) received bm1 skin grafts and were treated with CD160Ig (⧫, n = 5) or control-Ig (⧫; n = 5); Survival is shown by Kaplan-Meier plots.</p