Corrigendum: A New Immunosuppressive Molecule Emodin Induces both CD4+FoxP3+ and CD8+CD122+ Regulatory T Cells and Suppresses Murine Allograft Rejection.

[This corrects the article DOI: 10.3389/fimmu.2017.01519.].

A New Immunosuppressive Molecule Emodin Induces both CD4+FoxP3+ and CD8+CD122+ Regulatory T Cells and Suppresses Murine Allograft Rejection.

Due to vigorous alloimmunity, an allograft is usually rejected without any conventional immunosuppressive treatment. However, continuous global immunosuppression may cause severe side effects, including tumors and infections. Mounting evidence has shown that cyclosporine (CsA), a common immunosuppressant used in clinic, impedes allograft tolerance by dampening regulatory T cells (Tregs), although it inhibits allograft rejection at the same time. Therefore, it is necessary to seek an alternative immunosuppressive drug that spares Tregs with high efficiency in suppression but low toxicity. In this study, we investigated the capacity of emodin, an anthraquinone molecule originally extracted from certain natural plants, to prolong transplant survival in a mouse model and explored the cellular and molecular mechanisms underlying its action. We found that emodin significantly extended skin allograft survival and hindered CD3+ T cell infiltration in the allograft, accompanied by an increase in CD4+Foxp3+ and CD8+CD122+ Treg frequencies and numbers but a reduction in effector CD8+CD44highCD62Llow T cells in recipient mice. Emodin also inhibited effector CD8+ T cells proliferation in vivo. However, CD4+CD25+, but not CD8+CD122+, Tregs derived from emodin-treated recipients were more potent in suppression of allograft rejection than those isolated from control recipients, suggesting that emodin also enhances the suppressive function of CD4+CD25+ Tregs. Interestingly, depleting CD25+ Tregs largely reversed skin allograft survival prolonged by emodin while depleting CD122+ Tregs only partially abrogated the same allograft survival. Furthermore, we found that emodin hindered dendritic cell (DC) maturation and reduced alloantibody production posttransplantation. Finally, we demonstrated that emodin inhibited in vitro proliferation of T cells and blocked their mTOR signaling as well. Therefore, emodin may be a novel mTOR inhibitor that suppresses alloimmunity by inducing both CD4+FoxP3+ and CD8+CD122+ Tregs, suppressing alloantibody production, and hindering DC maturation. Thus, emodin is a newly emerging immunosuppressant and could be utilized in clinical transplantation in the future.

Effects of Cigarette Smoking on Transplant Survival: Extending or Shortening It?

Cigarette smoking (CS) regulates both innate and adaptive immunity and causes numerous diseases, including cardiovascular, respiratory, and autoimmune diseases, allergies, cancers, and transplant rejection. Therefore, smoking poses a serious challenge to the healthcare system worldwide. Epidemiological studies have always shown that CS is one of the major risk factors for transplant rejection, even though smoking plays redundant roles in regulating immune responses. The complex roles for smoking in immunoregulation are likely due to molecular and functional diversities of cigarette smoke components, including carbon monoxide (CO) and nicotine. Especially, CO has been shown to induce immune tolerance. Although CS has been shown to impact transplantation by causing complications and subsequent rejection, it is overlooked whether CS interferes with transplant tolerance. We have previously demonstrated that cigarette smoke exposure reverses long-term allograft survival induced by costimulatory blockade. Given that CS impacts both adaptive and innate immunity and that it hinders long-term transplant survival, our perspective is that CS impacts transplant tolerance. Here, we review impacts of CS on major immune cells that are critical for transplant outcomes and propose the cellular and molecular mechanisms underlying its effects on alloimmunity and transplant survival. Further investigations are warranted to fully understand why CS exerts deleterious rather than beneficial effects on transplant survival even if some of its components are immunosuppressive.

CD8(+)CD122(+) T-Cells: A Newly Emerging Regulator with Central Memory Cell Phenotypes.

CD8(+)CD122(+) T-cells have been traditionally described as antigen-specific memory T-cells that respond to previously encountered antigens more quickly and vigorously than their naïve counterparts. However, mounting evidence has demonstrated that murine CD8(+)CD122(+) T-cells exhibit a central memory phenotype (CD44(high)CD62L(high)), regulate T cell homeostasis, and act as regulatory T-cells (Treg) by suppressing both autoimmune and alloimmune responses. Importantly, naturally occurring murine CD8(+)CD122(+) Tregs are more potent in immunosuppression than their CD4(+)CD25(+) counterparts. They appear to be acting in an antigen-non-specific manner. Human CD8(+)CXCR3(+) T-cells are the equivalent of murine CD8(+)CD122(+) Tregs and also exhibit central memory phenotypes. In this mini-review article, we will summarize recent progresses in their phenotypes, homeostatic expansion, antigen-specificity, roles in the suppression of alloimmune and autoimmune responses, and the mechanisms underlying their inhibitory function.

Quenched Assembly of NIR-Active Gold Nanoclusters Capped with Strongly Bound Ligands by Tuning Particle Charge via pH and Salinity.

Gold nanospheres coated with a binary monolayer of bound citrate and cysteine ligands were assembled into nanoclusters, in which the size and near-infrared (NIR) extinction were tuned by varying the pH and concentration of added NaCl. During full evaporation of an aqueous dispersion of 4.5 ± 1.8 nm Au primary particles, the nanoclusters were formed and quenched by the triblock copolymer polylactic acid (PLA)(1K)-b-poly(ethylene glycol) (PEG)(10K)-b-PLA(1K), which also provided steric stabilization. The short-ranged depletion and van der Waals attractive forces were balanced against longer ranged electrostatic repulsion to tune the nanocluster diameter and NIR extinction. Upon lowering the pH from 7 to 5 at a given salinity, the magnitude of the charge on the primary particles decreased, such that the weaker electrostatic repulsion increased the hydrodynamic diameter and, consequently, NIR extinction of the clusters. At a given pH, as the concentration of NaCl was increased, the NIR extinction decreased monotonically. Furthermore, the greater screening of the charges on the nanoclusters weakened the interactions with PLA(1K)-b-PEG(10K)-b-PLA(1K) and thus lowered the amount of adsorbed polymer on the nanocluster surface. The generalization of the concept of self-assembly of small NIR-active nanoclusters to include a strongly bound thiol and the manipulation of the morphologies and NIR extinction by variation of pH and salinity not only is of fundamental interest but also is important for optical biomedical imaging and therapy.

Charged gold nanoparticles with essentially zero serum protein adsorption in undiluted fetal bovine serum.

The adsorption of even a single serum protein molecule on a gold nanosphere used in biomedical imaging may increase the size too much for renal clearance. In this work, we designed charged ~5 nm Au nanospheres coated with binary mixed-charge ligand monolayers that do not change in size upon incubation in pure fetal bovine serum (FBS). This lack of protein adsorption was unexpected in view of the fact that the Au surface was moderately charged. The mixed-charge monolayers were composed of anionic citrate ligands modified by place exchange with naturally occurring amino acids: either cationic lysine or zwitterionic cysteine ligands. The zwitterionic tips of either the lysine or cysteine ligands interact weakly with the proteins and furthermore increase the distance between the "buried" charges closer to the Au surface and the interacting sites on the protein surface. The ~5 nm nanospheres were assembled into ~20 nm diameter nanoclusters with strong near-IR absorbance (of interest in biomedical imaging and therapy) with a biodegradable polymer, PLA(1k)-b-PEG(10k)-b-PLA(1k). Upon biodegradation of the polymer in acidic solution, the nanoclusters dissociated into primary ~5 nm Au nanospheres, which also did not adsorb any detectable serum protein in undiluted FBS.

Equilibrium gold nanoclusters quenched with biodegradable polymers.

Although sub-100 nm nanoclusters of metal nanoparticles are of interest in many fields including biomedical imaging, sensors, and catalysis, it has been challenging to control their morphologies and chemical properties. Herein, a new concept is presented to assemble equilibrium Au nanoclusters of controlled size by tuning the colloidal interactions with a polymeric stabilizer, PLA(1k)-b-PEG(10k)-b-PLA(1k). The nanoclusters form upon mixing a dispersion of ~5 nm Au nanospheres with a polymer solution followed by partial solvent evaporation. A weakly adsorbed polymer quenches the equilibrium nanocluster size and provides steric stabilization. Nanocluster size is tuned from ~20 to ~40 nm by experimentally varying the final Au nanoparticle concentration and the polymer/Au ratio, along with the charge on the initial Au nanoparticle surface. Upon biodegradation of the quencher, the nanoclusters reversibly and fully dissociate to individual ~5 nm primary particles. Equilibrium cluster size is predicted semiquantitatively with a free energy model that balances short-ranged depletion and van der Waals attractions with longer-ranged electrostatic repulsion, as a function of the Au and polymer concentrations. The close spacings of the Au nanoparticles in the clusters produce strong NIR extinction over a broad range of wavelengths from 650 to 900 nm, which is of practical interest in biomedical imaging.