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"Paul, William E"
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The teaching and study of Islam in western universities
\"This book examines the teaching of Islam and the issues that raises inside universities for the academic community having to negotiate between competing cultural and philosophical demands\"-- Provided by publisher.
Book
S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense
Group 2 innate lymphoid cells (ILC2s) are a population of immune cells that play important roles in tissue homeostasis and barrier immunity to helminths. Recent work has suggested that ILC2s are primarily long-term residents of tissues that do not readily recirculate. Huang et al. now demonstrate, however, that these findings do not necessarily hold true for the interleukin-25 (IL-25)–responsive KLRG1 hi “inflammatory” ILC2 (iILC2) subset (see the Perspective by Mjösberg and Rao). In response to exogenous IL-25 or helminth infection, iILC2 precursors in the small intestinal lamina propria proliferate and alter their expression of sphingosine 1-phosphate (S1P) receptors. They then traffic to both lymphatic and nonlymphatic organs in a partly S1P-dependent manner, participating in vital anti-helminth and tissue repair responses. Science , this issue p. 114 ; see also p. 36 Innate lymphoid cells complement adaptive immunity by providing both local and distant tissue protection during infection. Innate lymphoid cells (ILCs) are innate counterparts of adaptive T lymphocytes, contributing to host defense, tissue repair, metabolic homeostasis, and inflammatory diseases. ILCs have been considered to be tissue-resident cells, but whether ILCs move between tissue sites during infection has been unclear. We show here that interleukin-25– or helminth-induced inflammatory ILC2s are circulating cells that arise from resting ILC2s residing in intestinal lamina propria. They migrate to diverse tissues based on sphingosine 1-phosphate (S1P)–mediated chemotaxis that promotes lymphatic entry, blood circulation, and accumulation in peripheral sites, including the lung, where they contribute to anti-helminth defense and tissue repair. This ILC2 expansion and migration is a behavioral parallel to the antigen-driven proliferation and migration of adaptive lymphocytes to effector sites and indicates that ILCs complement adaptive immunity by providing both local and distant tissue protection during infection.
Journal Article
Priced out : the economic and ethical costs of American health care
\"From a giant of health care policy, an engaging and enlightening account of why American health care is so expensive -- and why it doesn't have to be. Uwe Reinhardt was a towering figure and moral conscience of health care policy in the United States and beyond. Famously bipartisan, he advised presidents and Congress on health reform and originated central features of the Affordable Care Act. In Priced Out, Reinhardt offers an engaging and enlightening account of today's U.S. health care system, explaining why it costs so much more and delivers so much less than the systems of every other advanced country, why this situation is morally indefensible, and how we might improve it. The problem, Reinhardt says, is not one of economics but of social ethics. There is no American political consensus on a fundamental question other countries settled long ago: to what extent should we be our brothers' and sisters' keepers when it comes to health care? Drawing on the best evidence, he guides readers through the chaotic, secretive, and inefficient way America finances health care, and he offers a penetrating ethical analysis of recent reform proposals. At this point, he argues, the United States appears to have three stark choices: the government can make the rich help pay for the health care of the poor, ration care by income, or control costs. Reinhardt proposes an alternative path: that by age 26 all Americans must choose either to join an insurance arrangement with community-rated premiums, or take a chance on being uninsured or relying on a health insurance market that charges premiums based on health status. An incisive look at the American health care system, Priced Out dispels the confusion, ignorance, myths, and misinformation that hinder effective reform.\" -- Provided by publisher.
Book
Heterogeneity and plasticity of T helper cells
CD4 T helper （Th） cells play critical roles in adaptive immune responses. They recruit and activate other immune cells including B cells, CD8 T cells, macrophages, mast cells, neutrophils, eosinophils and basophils. Based on their functions, their pattern of cytokine secretion and their expression of specific transcription factors, Th cells, differentiated from naive CD4 T cells, are classified into four major lineages, Thl, Th2, Th17 and T regulatory （Treg） cells, although other Th lineages may exist. Subsets of the same lineage may express different effector cytokines, reside at different locations or give rise to cells with different fates, whereas cells from different lineages may secrete common cytokines, such as IL-2, IL-9 and IL-10, resulting in massive heterogeneity of the Th cell population. In addition, the pattern of cytokine secretion may switch from that of one lineage toward another under certain circumstances, suggesting that Th cells are plastic. Tregs are also more heterogeneous and plastic than were originally thought. In this review, we summarize recent reports on heterogeneity and plasticity of Th cells, and discuss potential mechanisms and implications of such features that Th cells display.
Journal Article
IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation
IL-1 causes a marked increase in the degree of expansion of naïve and memory CD4 T cells in response to challenge with their cognate antigen. The response occurs when only specific CD4 T cells can respond to IL-1β, is not induced by a series of other cytokines and does not depend on IL-6 or CD-28. When WT cells are primed in IL-1R1⁻/⁻ recipients, IL-1 increases the proportion of cytokine-producing transgenic CD4 T cells, especially IL-17- and IL-4-producing cells, strikingly increases serum IgE levels and serum IgG1 levels. IL-1β enhances antigen-mediated expansion of in vitro primed Th1, Th2, and Th17 cells transferred to IL-1R1⁻/⁻ recipients. The IL-1 receptor antagonist diminished responses to antigen plus lipopolysaccharide (LPS) by [almost equal to]55%. These results indicate that IL-1β signaling in T cells markedly induces robust and durable primary and secondary CD4 responses.
Journal Article
What determines Th2 differentiation, in vitro and in vivo?
We have known since 1991 how to induce naive CD4 T cells to differentiate in vitro into Th2 cells and, over the ensuing years, a comprehensive picture of the molecules involved in this important process has emerged. GATA3 and STAT5 are both essential for in vitro differentiation, stimulating naive cells through a process involving induction, which is T‐cell receptor (TCR) dependent but interleukin (IL)‐4 independent, and commitment, which is IL‐4 dependent. Th2 differentiation in vivo appears more complex. GATA3 and probably STAT5 are required in vivo but, at least for certain helminth infections, the IL‐4/IL‐4Ra/STAT6 pathway is dispensable. The role of thymic stromal lymphopoietin and of low TCR signal strength and the participation of basophils in establishing a Th2‐baising in vivo environment have achieved considerable attention. Here I discuss the major players in Th2 differentiation particularly as they may exert their effects in vivo.
Journal Article
GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors
Naïve CD4 T cells can differentiate into at least two different types of T helpers, Th1 and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including Stat5, Gfi-1 and GATA-3. Stat5 activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stat5 signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional
Gata3
knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation (both IL-4 dependent and IL-4 independent) and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Th1 differentiation.
Journal Article
Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses
Expression of the transcription factor GATA-3 is strongly associated with T helper type 2 (T
H
2) differentiation, but genetic evidence for its involvement in this process has been lacking. Here, we generated a conditional GATA-3-deficient mouse line.
In vitro
deletion of
Gata3
diminished both interleukin 4 (IL-4)–dependent and IL-4-independent T
H
2 cell differentiation; without GATA-3, T
H
1 differentiation occurred in the absence of IL-12 and interferon-γ.
Gata3
deletion limited the growth of T
H
2 cells but not T
H
1 cells. Deletion of
Gata3
from established T
H
2 cells abolished IL-5 and IL-13 but not IL-4 production.
In vivo
deletion of
Gata3
using OX40-Cre eliminated T
H
2 responses and allowed the development of interferon-γ-producing cells in mice infected with
Nippostrongylus brasiliensis
. Thus, GATA-3 serves as a principal switch in determining T
H
1-T
H
2 responses.
Journal Article
Interleukin 2 plays a central role in Th2 differentiation
Differentiation of naïve CD4 T cells into T helper (Th) 2 cells requires signaling through the T cell receptor and an appropriate cytokine environment. IL-4 is critical for such Th2 differentiation. We show that IL-2 plays a central role in this process. The effect of IL-2 on Th2 generation does not depend on its cell growth or survival effects. Stat5 a-/-cells show diminished differentiation to IL-4 production, and forced expression of a constitutively active form of Stat5a replaces the need for IL-2. In vivo IL-2 neutralization inhibits IL-4 production in two models. Studies of restriction enzyme accessibility and binding of Stat5 to chromatin indicate that IL-2 mediates its effect by stabilizing the accessibility of the Il4 gene. Thus, IL-2 plays a critical role in the polarization of naive CD4 T cells to the Th2 phenotype.
Journal Article
Memory Phenotype CD4 T Cells Undergoing Rapid, Nonburst-Like, Cytokine-Driven Proliferation Can Be Distinguished from Antigen-Experienced Memory Cells
Memory phenotype (CD44(bright), CD25(negative)) CD4 spleen and lymph node T cells (MP cells) proliferate rapidly in normal or germ-free donors, with BrdU uptake rates of 6% to 10% per day and Ki-67 positivity of 18% to 35%. The rapid proliferation of MP cells stands in contrast to the much slower proliferation of lymphocytic choriomeningitis virus (LCMV)-specific memory cells that divide at rates ranging from <1% to 2% per day over the period from 15 to 60 days after LCMV infection. Anti-MHC class II antibodies fail to inhibit the in situ proliferation of MP cells, implying a non-T-cell receptor (TCR)-driven proliferation. Such proliferation is partially inhibited by anti-IL-7Rα antibody. The sequence diversity of TCRβ CDR3 gene segments is comparable among the proliferating and quiescent MP cells from conventional and germ-free mice, implying that the majority of proliferating MP cells have not recently derived from a small cohort of cells that expand through multiple continuous rounds of cell division. We propose that MP cells constitute a diverse cell population, containing a subpopulation of slowly dividing authentic antigen-primed memory cells and a majority population of rapidly proliferating cells that did not arise from naïve cells through conventional antigen-driven clonal expansion.
Journal Article