Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.

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Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

CA : A Cancer Journal for Clinicians

BackgroundMost patients with locally advanced, unresectable, non–small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti–programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. MethodsWe randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective res...

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Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

PLoS BIOLOGY Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor Jean-Philippe Coppe 1 , Christopher K. Patil 1[ , Francis Rodier 1,2[ , Yu Sun 3 , Denise P. Mun oz 1,2 , Joshua Goldstein 1¤ , Peter S. Nelson 3 , Pierre-Yves Desprez 1,4 , Judith Campisi 1,2* 1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, 2 Buck Institute for Age Research, Novato, California, United States of America, 3 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 4 California Pacific Medical Center Research Institute, San Francisco, California, United States of America Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA- damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment. Citation: Coppe JP, Patil CK, Rodier F, Sun Y, Mun oz DP, et al. (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6(12): e301. doi:10.1371/journal.pbio.0060301 Introduction Cancer is a multistep disease in which cells acquire increasingly malignant phenotypes. These phenotypes are acquired in part by somatic mutations, which derange normal controls over cell proliferation (growth), survival, invasion, and other processes important for malignant tumorigenesis [1]. In addition, there is increasing evidence that the tissue microenvironment is an important determinant of whether and how malignancies develop [2,3]. Normal tissue environ- ments tend to suppress malignant phenotypes, whereas abnormal tissue environments such at those caused by inﬂammation can promote cancer progression. Cancer development is restrained by a variety of tumor suppressor genes. Some of these genes permanently arrest the growth of cells at risk for neoplastic transformation, a process termed cellular senescence [4–6]. Two tumor suppressor pathways, controlled by the p53 and p16INK4a/pRB proteins, regulate senescence responses. Both pathways integrate multiple aspects of cellular physiology and direct cell fate towards survival, death, proliferation, or growth arrest, depending on the context [7,8]. Several lines of evidence indicate that cellular senescence is a potent tumor-suppressive mechanism [4,9,10]. Many poten- tially oncogenic stimuli (e.g., dysfunctional telomeres, DNA PLoS Biology | www.plosbiology.org damage, and certain oncogenes) induce senescence [6,11]. Moreover, mutations that dampen the p53 or p16INK4a/pRB pathways confer resistance to senescence and greatly increase cancer risk [12,13]. Most cancers harbor mutations in one or both of these pathways [14,15]. Lastly, in mice and humans, a senescence response to strong mitogenic signals, such as those delivered by certain oncogenes, prevents premalignant lesions from progressing to malignant cancers [16–19]. Academic Editor: Julian Downward, Cancer Research UK, United Kingdom Received June 27, 2008; Accepted October 22, 2008; Published December 2, 2008 Copyright: O 2008 Coppe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abbreviations: CM, conditioned medium; DDR, DNA damage response; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial–mesenchymal transition; GSE, genetic suppressor element; IL, interleukin; MIT, mitoxantrone; PRE, presenescent; PrEC, normal human prostate epithelial cell; REP, replicative exhaustion; SASP, senescence-associated secretory phenotype; SEN, senescent; shRNA, short hairpin RNA; XRA, X-irradiation * To whom correspondence should be addressed. E-mail: jcampisi@lbl.gov [ These authors contributed equally to this work. ¤ Current address: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America December 2008 | Volume 6 | Issue 12 | e301

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

EVOLUTION: Of Mice . . .

The p63 gene regulates thymic epithelial cell (TEC) proliferation, whereas FoxN1 regulates their differentiation. However, their collaborative role in the regulation of TEC homeostasis during thymic aging is largely unknown. In murine models, the proportion of TAp63+, but not ΔNp63+, TECs was increased with age, which was associated with an age-related increase in senescent cell clusters, characterized by SA-β-Gal+ and p21+ cells. Intrathymic infusion of exogenous TAp63 cDNA into young wild-type (WT) mice led to an increase in senescent cell clusters. Blockade of TEC differentiation via conditional FoxN1 gene knockout accelerated the appearance of this phenotype to early middle age, whereas intrathymic infusion of exogenous FoxN1 cDNA into aged WT mice brought only a modest reduction in the proportion of TAp63+ TECs, but an increase in ΔNp63+ TECs in the partially rejuvenated thymus. Meanwhile, we found that the increased TAp63+ population contained a high proportion of phosphorylated-p53 TECs, which may be involved in the induction of cellular senescence. Thus, TAp63 levels are positively correlated with TEC senescence but inversely correlated with expression of FoxN1 and FoxN1-regulated TEC differentiation. Thereby, the p63-FoxN1 regulatory axis in regulation of postnatal TEC homeostasis has been revealed.

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Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging

Mutation in the “nude” gene, i.e. the FoxN1 gene, induces a hairless phenotype and a rudimentary thymus gland in mice (nude mouse) and humans (T-cell related primary immunodeficiency). Conventional FoxN1 gene knockout and transgenic mouse models have been generated for studies of FoxN1 gene function related to skin and immune diseases, and for cancer models. It appeared that FoxN1’s role was fully understood and the nude mouse model was fully utilized. However, in recent years, with the development of inducible gene knockout/knockin mouse models with the loxP-Cre(ER T ) and diphtheria toxin receptor-induced cell abolished systems, it appears that the complete repertoire of FoxN1’s roles and deep-going usage of nude mouse model in immune function studies have just begun. Here we summarize the research progress made by several recent works studying the role of FoxN1 in the thymus and utilizing nude and “second (conditional) nude” mouse models for studies of T-cell development and function. We also raise questions and propose further consideration of FoxN1 functions and utilizing this mouse model for immune function studies.

/pdf/insights-on-foxn1-biological-significance-and-usages-of-the-pp6c31nff3.pdf

Insights on Foxn1 biological significance and usages of the "nude" mouse in studies of T-Lymphopoiesis

Postnatal thymic epithelial cell (TEC) homeostatic defect- or natural aging-induced thymic atrophy results in a decline in central T-cell tolerance establishment, which is constituted by thymocyte negative selection and cluster of differentiation (CD) 4+ thymic regulatory T (tTreg) cell generation. Emerging evidence shows this decline mainly results from defects in negative selection, but there is insufficient evidence regarding whether tTreg cell generation is also impaired. We mechanistically studied tTreg cell generation in the atrophied thymus by utilizing both postnatal TEC-defective (resulting from FoxN1-floxed conditional knockout [cKO]) and naturally aged mouse models. We found that the capacity of tTreg cell generation was not impaired compared to CD4+ thymic conventional T cells, suggesting thymic atrophy positively influences tTreg cell generation. This is potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary TECs, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age-related diseases could take place.

/pdf/capacity-of-ttreg-generation-is-not-impaired-in-the-57y46meosb.pdf

Capacity of tTreg generation is not impaired in the atrophied thymus.

Immunosenescence: a product of the environment?

// Brandon Coder 1,* , Weikan Wang 1,2,* , Liefeng Wang 1,3 , Zhongdao Wu 4 , Qichuan Zhuge 2 and Dong-Ming Su 1 1 Institute of Molecular Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA 2 Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, First Affiliated Hospital, Wenzhou Medical University, Wenzhou City, Zhejiang, P. R. China 3 Department of Biotechnology, Gannan Medical University, Ganzhou, P. R. China 4 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P. R. China * These authors have contributed equally to this work Correspondence to: Dong-Ming Su, email: // Qichuan Zhuge, email: // Keywords : T-cell immunity; aging; neurodegeneration; immunotherapy Received : August 17, 2016 Accepted : October 05, 2016 Published : October 11, 2016 Abstract The interaction between T cells and the central nervous system (CNS) in homeostasis and injury has been recognized being both pathogenic (CD4 + T-helper 1 - Th1, Th17 and γδT) and ameliorative (Th2 and regulatory T cells - Tregs). However, in-depth studies aimed to elucidate the precise in the aged microenvironment and the dichotomous role of Tregs have just begun and many aspects remain unclear. This is due, not only to a mutual dependency and reciprocal causation of alterations and diseases between the nervous and T cell immune systems, but also to an inconsistent aging of the two systems, which dynamically changes with CNS injury/recovery and/or aging process. Cellular immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution - sources of chronic inflammation in the elderly (termed inflammaging), potentially induces an acceleration of brain aging and memory loss. In turn, aging of the brain via neuro-endocrine-immune network drives total body systemic aging, including that of the immune system. Therefore, immunotherapeutics including vaccination and “protective autoimmunity” provide promising means to rejuvenate neuro-inflammatory disorders and repair CNS acute injury and chronic neuro-degeneration. We review the current understanding and recent discoveries linking the aging immune system with CNS injury and neuro-degeneration. Additionally, we discuss potential recovery and rejuvenation strategies, focusing on targeting the aging T cell immune system in an effort to alleviate acute brain injury and chronic neuro-degeneration during aging, via the “thymus-inflammaging-neurodegeneration axis”.

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Dong-Ming Su

Papers

Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging

Insights on Foxn1 biological significance and usages of the "nude" mouse in studies of T-Lymphopoiesis

Capacity of tTreg generation is not impaired in the atrophied thymus.

Immunosenescence: a product of the environment?

Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging