The main targets for the immunosuppressive calcineurin inhibitors, cyclosporin A (CsA) and tacrolimus, have been considered to be activated T cells, but not antigen-presenting cells. Here we demonstrate that CsA and tacrolimus, but not rapamycin, inhibit major histocompatibility complex (MHC)-restricted antigen presentation in dendritic cells (DCs). Microencapsulated ovalbumin (OVA) was efficiently captured, processed, and presented on both class I MHC molecules IntroductionDendritic cells (DCs) play a key role in the initiation of primary immune responses. 1 DCs can acquire and process antigens in the periphery, and migrate to secondary lymphoid tissues where they prime primary T-cell responses. Two distinct pathways have been known for the presentation of antigenic peptides on major histocompatibility complex (MHC) molecules. 2 Exogenous antigens internalized by phagocytosis or endocytosis are normally processed and loaded on class II MHC molecules in a post-Golgi compartment. In contrast, endogenous antigens are partially digested by proteosome, transferred into endoplasmic reticulum (ER) by a transporter associated with antigen presentation (TAP), and then loaded on class I MHC molecules. It is also known that DCs can uptake antigens from cells undergoing apoptosis or necrosis for presentation to class I MHC-restricted cytotoxic T lymphocytes (CTLs). This form of antigen presentation has been termed "cross-presentation." Crosspresentation has been demonstrated to occur for many viral antigens and also for tumor antigens. 3,4 Cross-presentation may be a mechanism by which naive T cells can be primed to antigens that are present in nonprofessional antigen-presenting cells (APCs). In the absence of such a mechanism, viral or tumor antigens expressed in nonprofessional APCs could escape immunosurveillance because CTL responses can only be induced efficiently for the antigens presented via class I MHC molecules on professional APCs. [5][6][7] Thus far, the main cellular targets for CsA and tacrolimus have been considered to be activated T cells, but not APCs. 8 Even though chemically unrelated, CsA and tacrolimus bind to and inhibit the same protein, calcineurin, in a calcium-dependent signaling pathway after formation of a complex with cyclophilin A and FK-506 binding proteins (FKBPs), respectively, resulting in inhibition of the transcription of interleukin 2 (IL-2) and other lymphokines. 9,10 Rapamycin has structural similarity with tacrolimus and even forms a complex with the same FKBPs that form a complex with tacrolimus. 11 However, the FKBP-rapamycin complex interacts with a protein distinct from calcineurin, termed the mammalian target of rapamycin, mTOR. 12 Rapamycin suppresses T-cell activation at a different level, mainly through inhibition of cell-cycle progression via suppression of p70 S6 kinase activation induced by growthpromoting lymphokines. 8 Because T-cell responses can only be initiated on recognition of peptide-MHC complexes presented by professional APCs, inhibitors of antigen processing p...

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Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice, subsequently suppressing the host immune system. MDSCs represent a group of immature myeloid cells expressing CD11b and Gr-1. Here, we show that a Toll-like receptor (TLR) agonist, resiquimod, which binds to TLR7 and TLR8, induces the differentiation of MDSCs into mature myeloid cells. MDSCs were isolated from mice bearing mammary carcinoma 4T1 cells, and the purified MDSCs were cultured in the presence of resiquimod for 5 days. Phenotypic analysis showed that the resiquimod-treated MDSCs differentiated into F4/80⁺ macrophages and CD11c⁺/I-A(d⁺) dendritic cells. Functional analysis showed that the MDSCs also lost their suppressive activity on T cells. Resiquimod-treated MDSCs significantly enhanced the proliferation of T cells that were treated with anti-CD3 and anti-CD28 monoclonal antibodies. These results show that resiquimod induces the differentiation of MDSCs into macrophages and dendritic cells, and also suggest that resiquimod may improve cancer immunotherapy by reducing immunosuppressive MDSCs.

We study the decay and smoothness of solutions of the dispersion managed non-linear Schrödinger equation in the case of zero residual dispersion. Using new x-space versions of bilinear Strichartz estimates, we show that the solutions are not only smooth, but also fast decaying.

Abstract. We study Schrödinger operator H = −∆ + V (x) in dimension two, V (x) being a limit-periodic potential. We prove that the spectrum of H contains a semiaxis and there is a family of generalized eigenfunctions at every point of this semiaxis with the following properties. First, the eigenfunctions are close to plane waves e i k, x at the high energy region. Second, the isoenergetic curves in the space of momenta k corresponding to these eigenfunctions have a form of slightly distorted circles with holes (Cantor type structure). Third, the spectrum corresponding to the eigenfunctions (the semiaxis) is absolutely continuous.

We give a simple proof of existence of solutions of the dispersion management and diffraction management equations for zero average dispersion, respectively diffraction. These solutions are found as maximizers of non-linear and non-local variational problems which are invariant under a large non-compact group. Our proof of existence of maximizer is rather direct and avoids the use of Lions' concentration compactness argument or Ekeland's variational principle.

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We prove a threshold phenomenon for the existence of solitary solutions of the dispersion management equation for positive and zero average dispersion for a large class of nonlinearities. These solutions are found as minimizers of nonlinear and nonlocal variational problems which are invariant under a large non-compact group. There exists a threshold such that minimizers exist when the power of the solitons is bigger than the threshold. Our proof of existence of minimizers is rather direct and avoids the use of Lions' concentration compactness argument. The existence of dispersion managed solitons is shown under very mild conditions on the dispersion profile and the nonlinear polarization of optical active medium, which cover all physically relevant cases for the dispersion profile and a large class of nonlinear polarizations, for example, they are allowed to change sign.