Tumoricidal efficacy coincides with CD11c up-regulation in antigen-specific CD8+ T cells during vaccine immunotherapy

Background: Dendritic cells (DCs) mount tumor-associated antigens (TAAs), and the double-stranded RNA adjuvant Poly(I:C) stimulates Toll-like receptor 3 (TLR3) signal in DC, which in turn induces type I interferon (IFN) and interleukin-12 (IL-12), then cross-primes cytotoxic T lymphocytes (CTLs). Proliferation of CTLs correlates with tumor regression. How these potent cells expand with high quality is crucial to the outcome of CTL therapy. However, good markers reflecting the efficacy of DC-target immunotherapy have not been addressed. Methods: Using an EG7 (ovalbumin, OVA-positive) tumor-implant mouse model, we examined what is a good marker for active CTL induction in treatment with Poly(I:C)/OVA. Results: Simultaneous administration of Poly(I:C) and antigen (Ag) OVA significantly increased a minor population of CD8+ T cells, that express CD11c in lymphoid and tumor sites. The numbers of the CD11c+ CD8+ T cells correlated with those of induced Ag-specific CD8+ T cells and tumor regression. The CD11c+ CD8+ T cell moiety was characterized by its high killing activity and IFN-γ-producing ability, which represent an active phenotype of the effector CTLs. Not only a TLR3-specific (TICAM-1-dependent) signal but also TLR2 (MyD88) signal in DC triggered the expansion of CD11c+ CD8+ T cells in tumor-bearing mice. Notably, human CD11c+ CD8+ T cells also proliferated in peripheral blood mononuclear cells (PBMC) stimulated with cytomegalovirus (CMV) Ag. Conclusions: CD11c expression in CD8+ T cells reflects anti-tumor CTL activity and would be a marker for immunotherapeutic efficacy in mouse models and probably cancer patients as well

Triaxial deformation in 10Be

The triaxial deformation in $^{10}$Be is investigated using a microscopic $\alpha+\alpha+n+n$ model. The states of two valence neutrons are classified based on the molecular-orbit (MO) model, and the $\pi$-orbit is introduced about the axis connecting the two $\alpha$-clusters for the description of the rotational bands. There appear two rotational bands comprised mainly of $K^\pi = 0^+$ and $K^\pi = 2^+$, respectively, at low excitation energy, where the two valence neutrons occupy $K^\pi = 3/2^-$ or $K^\pi = 1/2^-$ orbits. The triaxiality and the $K$-mixing are discussed in connection to the molecular structure, particularly, to the spin-orbit splitting. The extent of the triaxial deformation is evaluated in terms of the electro-magnetic transition matrix elements (Davydov-Filippov model, Q-invariant model), and density distribution in the intrinsic frame. The obtained values turned out to be $\gamma = 15^o \sim 20^o$.Comment: 15 pages, latex, 3 figure

Structure of Excited States of 10Be studied with Antisymmetrized Molecular Dynamics

We study structure of excited states of 10Be with the method of variation after spin parity projection in the framework of antisymmetrized molecular dynamics. Present calculations describe many excited states and reproduce the experimental data of E2 and E1 transitions and the new data of the $\beta$ transition strength successfully. We make systematic discussions on the molecule-like structures of light unstable nuclei and the important role of the valence neutrons based on the results obtained with the framework which is free from such model assumptions as the existence of inert cores and clusters.Comment: 15 pages, RevTex, seven postscript figures (using epsf.sty

Important role of the spin-orbit interaction in forming the 1/2^+ orbital structure in Be isotopes

The structure of the second 0^+ state of ^{10}Be is investigated using a microscopic $\alpha+\alpha+n+n$ model based on the molecular-orbit (MO) model. The second 0^+ state, which has dominantly the (1/2^+)^2 configuration, is shown to have a particularly enlarged $\alpha-\alpha$ structure. The kinetic energy of the two valence neutrons occupying along the $\alpha-\alpha$ axis is reduced remarkably due to the strong $\alpha$ clustering and, simultaneously, the spin-orbit interaction unexpectedly plays important role to make the energy of this state much lower. The mixing of states with different spin structure is shown to be important in negative-parity states. The experimentally observed small-level spacing between 1^- and 2^- (~ 300 keV) is found to be an evidence of this spin-mixing effect. ^{12}{Be} is also investigated using $\alpha+\alpha+4n$ model, in which four valence neutrons are considered to occupy the (3/2^-)^2(1/2^+)^2 configuration. The energy surface of ^{12}Be is shown to exhibit similar characteristics, that the remarkable $\alpha$ clustering and the contribution of the spin-orbit interaction make the binding of the state with (3/2^-)^2(1/2^+)^2 configuration properly stronger in comparison with the closed p-shell (3/2^-)^2(1/2^-)^2 configuration.Comment: 14 pages, 4 figure

Linear response theory in the continuum for deformed nuclei: Green's function vs. time-dependent Hartree-Fock with the absorbing-boundary condition

The continuum random-phase approximation is extended to the one applicable to deformed nuclei. We propose two different approaches. One is based on the use of the three dimensional (3D) Green's function and the other is the small-amplitude TDHF with the absorbing-boundary condition. Both methods are based on the 3D Cartesian grid representation and applicable to systems without any symmetry on nuclear shape. The accuracy and identity of these two methods are examined with the BKN interaction. Using the full Skyrme energy functional in the small-amplitude TDHF approach, we study the isovector giant dipole states in the continuum for O-16 and for even-even Be isotopes.Comment: 15 pages, 8 figure

Structure of excited states of Be-11 studied with Antisymmetrized Molecular Dynamics

The structures of the ground and excited states of Be-11 were studied with a microscopic method of antisymmetrized molecular dynamics. The theoretical results reproduce the abnormal parity of the ground state and predict various kinds of excited states. We suggest a new negative-parity band with a well-developed clustering structure which reaches high-spin states. Focusing on a $2\alpha$ clustering structure, we investigated structure of the ground and excited states. We point out that molecular orbits play important roles for the intruder ground state and the low-lying $2\hbar \omega$ states. The features of the breaking of $\alpha$ clusters were also studied with the help of data for Gamow-Teller transitions.Comment: 24 pages, 7 figures, to be submitted to Phys.Rev.

The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation

Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated.Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually.We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails