Rockefeller University

About: Rockefeller University is a education organization based out in New York, New York, United States. It is known for research contribution in the topics: Population & Gene. The organization has 15867 authors who have published 32938 publications receiving 2940261 citations. The organization is also known as: Rockefeller University & Rockefeller Institute.

Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

Abstract: An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

Curvature and the Eigenvalues of the Laplacian

Abstract: A famous formula of H. Weyl [17] states that if D is a bounded region of R d with a piecewise smooth boundary B, and if 0 > γ1 ≥ γ2 ≥ γ3 ≥ etc. ↓−∞ is the spectrum of the problem $$\displaystyle\begin{array}{rcl} \varDelta f =\big (\partial ^{2}/\partial x_{ 1}^{2} + \cdots + \partial ^{2}/\partial x_{ d}^{2}\big)f =\gamma f\quad \mbox{ in }D,& &{}\end{array}$$ (6.1.1a) $$\displaystyle\begin{array}{rcl} f \in C^{2}(D) \cap C(\overline{D}),& &{}\end{array}$$ (6.1.1b) $$\displaystyle\begin{array}{rcl} f = 0\quad \mbox{ on }B,& &{}\end{array}$$ (6.1.1c) then $$\displaystyle\begin{array}{rcl} -\gamma _{n} \sim C(d)(n/\mbox{ vol }D)^{2/d}\quad (n \uparrow \infty ),& &{}\end{array}$$ (6.1.2) or, what is the same, $$\displaystyle\begin{array}{rcl} Z \equiv \mathop{\mathrm{sp}} olimits e^{t\varDelta } =\sum _{ n\geq 1}\exp \big(\gamma _{n}t\big) \sim (4\pi t)^{-d/2} \times \mathop{\mathrm{vol}} olimits D\quad (t \downarrow 0),& &{}\end{array}$$ (6.1.3) where \(C(d) = 2\pi [(d/2)!]^{d/2}\).

Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons

Abstract: Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.