Prenatal tolerance – a role for regulatory T cells?

Regulatory T cells (TR cells) play a major role in controlling immune self reactivity. However, little is known about their occurrence and functions in early developmental stages. In this issue of the European Journal of Immunology, Cupedo et al. report the presence of functional CD4+CD25+ TR cells in the human fetus. In contrast to previous studies, the analysis is performed on fetal thymus, spleen and lymph node samples in addition to cord blood cells. Interestingly, TR cells are present in all these organs from 14 weeks of gestation, along with FoxP3 (forkhead box protein 3) RNA, a marker for naturally arising TR cells. The fetal TR cells show, however, phenotypic differences depending on their location, possibly because of variations in their activation state. The emergence of TR cells so early in fetal development raises a number of questions about the mechanisms of self reactivity and tolerance in the prenatal stages, which may have important implications for our understanding of childhood pathologies.     

CD52 as both a marker and an effector molecule of T cells with regulatory action： Identification of novel regulatory T cells

Regulation of immune responses is central to an effective clearance of pathogens. An effective immune response is also necessary for preventing the development of cancer and auto- immune diseases and for maintaining homeostasis. Although the thymus is the central lymphoid organ that regulates immune responses for self-tol- erance during the maturation of T cells, regulatory immune cells are still required for the proper functioning of mature immune cells in the periphery. Regulatory cells are a subpopulation of immune cells that suppress proliferation and cytokine production by other immune cells in res- ponse to antigenic stimulation.     

Is the search for alternative sources of human pluripotent stem cells a mistake?

One response to the controversy in the United States over the moral status of the early embryo has been the proposal that scientists search for alternative sources of pluripotent stem cells. Is this a good idea? The present article argues that it is not. Following a brief look at the ethical standing of the four proposals assessed by the President’s Council on Bioethics in 2005, the author addresses the fundamental question of the wisdom of pursuing alternatives to current methods of stem cell derivation. The author concludes that, given the poor prospects for finding alternatives that are both scientifically and ethically sound, and the costs of diverting energy and resources from established embryonic methods, further investment in the search for alternative methods is unwise.     

Tolerance in mixed chimerism – a role for regulatory cells?

The establishment of mixed hematopoietic chimerism induces life-long donor-specific organ graft tolerance while obviating the need for chronic immunosuppression. Recent advances have dramatically reduced the conditioning toxicity required to achieve mixed chimerism. We argue that the achievement of high levels of donor chimerism ensures life-long deletion of donor-reactive T cells, precluding and obviating the need for regulatory mechanisms in the maintenance of tolerance. However, in situations where high levels of donor chimerism cannot be established or sustained, control of immune responsiveness can be achieved through additional mechanisms, including regulatory T cells.     

Is smoking-related attentional bias a useful marker for treatment effects?

Theoretical models of nicotine abuse suggest that preferential attention allocation towards smoking-related stimuli plays an important role in the development and maintenance of smoking behavior. However, little is known about the impact of standard treatment programs for nicotine cessation on this effect. In the current study, we investigated smoking-related attentional bias using a visual dot probe task and an emotional Stroop task before and after a standard behavioral group therapy. Smokers (n=39) who received treatment, a smoker control group without treatment (n=20) and a non-smoker control group (n=20) were investigated. Although we found a reduction in attentional bias scores after successful treatment, this effect failed to reach statistical significance. Of note, we observed a low test-retest reliability in low-dependence smokers in both tasks which is a substantial limitation for using these paradigms in longitudinal studies. Additionally, there was no significant correlation between the attentional bias scores from both tasks.     

The pluripotency factor LIN28 in monkey and human testes: a marker for spermatogonial stem cells?

Mammalian spermatogenesis is maintained by spermatogonial stem cells (SSCs). However, since evidentiary assays and unequivocal markers are still missing in non-human primates (NHPs) and man, the identity of primate SSCs is unknown. In contrast, in mice, germ cell transplantation studies have functionally demonstrated the presence of SSCs. LIN28 is an RNA-binding pluripotent stem cell factor, which is also strongly expressed in undifferentiated mouse spermatogonia. By contrast, two recent reports indicated that LIN28 is completely absent from adult human testes. Here, we analyzed LIN28 expression in marmoset monkey (Callithrix jacchus) and human testes during development and adulthood and compared it with that in mice. In the marmoset, LIN28 was strongly expressed in migratory primordial germ cells and gonocytes. Strikingly, we found a rare LIN28-positive subpopulation of spermatogonia also in adult marmoset testis. This was corroborated by western blotting and quantitative RT-PCR. Importantly, in contrast to previous publications, we found LIN28-positive spermatogonia also in normal adult human and additional adult NHP testes. Some seasonal breeders exhibit a degenerated (involuted) germinal epithelium consisting only of Sertoli cells and SSCs during their non-breeding season. The latter re-initiate spermatogenesis prior to the next breeding-season. Fully involuted testes from a seasonal hamster and NHP (Lemur catta) exhibited numerous LIN28-positive spermatogonia, indicating an SSC identity of the labeled cells. We conclude that LIN28 is differentially expressed in mouse and NHP spermatogonia and might be a marker for a rare SSC population in NHPs and man. Further characterization of the LIN28-positive population is required.     

How many mechanisms do regulatory T cells need?

A plethora of new regulatory T cell (Treg) mechanisms have recently emerged. This raises two important questions. First, how many molecules or mechanisms are required for Treg to work? Second, how should we evaluate the contribution of any given Treg molecule/mechanism and how is this likely to relate (or not) to the phenotype seen in Scurfy/Foxp3‐deficient mice? In this discussion piece, I will briefly outline our current understanding of the Treg arsenal and address these important questions. See accompanying commentary: http://dx.doi.org/10.1002/eji.200838143     

Are CD8+CD122+ cells regulatory T cells or memory T cells?

We identified CD8(+)CD122(+) regulatory T cells in the mouse. Some immunologists consider CD8(+)CD122(+) cells to be memory T cells despite our report of their regulatory function. Here, we propose a dual phenotype of these cells. Murine CD8(+)CD122(+) T cells demonstrate both memory and regulatory features in their functional profiles. Human CD8(+)CXCR3(+) T cells, which are thought to be the human counterpart of murine CD8(+)CD122(+) regulatory T cells, do not match human central memory T cells of the CD8(+)CD45RA(-)CCR7(+) phenotype. Thus, we must consider human CD8(+) regulatory T cells and murine CD8(+) regulatory T cells separately. Of human CD8(+) regulatory T cells, CD8(+)CXCR3(+) regulatory T cells can be divided into further subsets and we may be able to distinguish memory T cells and regulatory T cells. Of murine CD8(+)CD122(+) regulatory T cells, it seems to be impossible to divide CD8(+)CD122(+)CD44(+)CD62L(+) regulatory T cells into further subsets at present, indicating that this single population of cells has activities of both regulatory T cells and memory T cells.     

Is immunotherapy-induced birch-pollen-specific IgG4 a marker for decreased allergen-specific sensitivity?

BACKGROUND: The role of IgG4 during allergen-specific immunotherapy (SIT) is still controversial. The available studies present paramount differences in in vitro techniques, allergens, and clinical outcome parameters. By implementing a sensitive method, and pivotal clinical outcome parameters, we wanted to ascertain the utility of IgG4 as a clinical marker of decreased allergen-specific sensitivity to a common aeroallergen. METHODS: Sera were drawn from 23 birch-pollen-allergic patients during a placebo-controlled clinical trial on birch pollen SIT. Seventeen patients received active treatment. Blood samples were drawn at 0, 2, 4, 7, and 30 treatment weeks, and 36 months. The binding activity of autologous IgG, IgG4, IgE, and IgE- and/or IgG-depleted serum to (125)I-labelled recombinant Bet v 1 was assessed in a fluid-phase radioimmunoassay. Disease severity was assessed subjectively on a visual analogue scale (VAS), and objectively by intradermal late-phase reaction diameters. RESULTS: Before SIT IgG4 fraction of IgG-allergen binding varied from 4 to 74%, with a median of 36%, increasing to 71% after 36 months. Changes in IgG4 or IgG4/IgG fraction were not correlated to clinical outcome parameters. Changes in IgG allergen binding and VAS were significantly correlated (sigma = 0.72; p < 0.05). SIT increased the serum-blocking activity of IgE allergen binding from 25% before SIT to 80% after SIT. No changes were observed in the placebo group. CONCLUSION: The data suggest that IgG4 per se is a poor marker of decreased allergen-specific sensitivity to birch pollen, both as a single measurement and as delta values.     

Do regulatory T cells play a role in the control of homeostatic proliferation?

The control of peripheral lymphocyte numbers is a fundamental aspect of the immune system. Regulatory T cells are involved in the suppression of autoimmune, antitumor, allergic, and other inflammatory responses, as well as in facilitating graft acceptance. In this paper, we discuss whether the control of homeostatic proliferation is another facet of the immune system that is controlled by regulatory T cells. A review of the published data connecting regulatory T cells with the control of homeostatic proliferation indicates that several key questions remain open. One of these relates to the stage at which regulatory T cells could play a role (i.e., T-cell proliferation vs. survival).     

Are dendritic cells central to regulatory T cell function?

The role of dendritic cells (DCs) as sentinels and inducers of immunity has been amply documented in the past 35 years. More recently, experimental evidence has suggested that DCs may also be critical to maintain tolerance to self-antigens. These opposing functions are complementary and would ensure the integrity of the organism in an environment full of pathogens. In this review, we summarize the observations supporting the hypothesis that DCs induce and maintain tolerance by a mechanism involving regulatory T cells.     

Are regulatory T cells the target of venom immunotherapy?

PURPOSE OF REVIEW: Allergen-specific immunotherapy is the only treatment that leads to lifelong tolerance to previously disease-causing allergens by restoring normal immunity against allergens. T-regulatory (TReg) cells are involved in preventing sensitization to allergens and represent a major target for venom- or other allergen-specific immunotherapy. RECENT FINDINGS: Induction of peripheral tolerance in T cells, which is characterized mainly by suppressed proliferative and cytokine responses against the T-cell epitopes of major allergens, is an essential step in specific immunotherapy. It is initiated by the autocrine action of interleukin-10 and/or transforming growth factor-beta, which are produced by antigen-specific TReg cells. Tolerized T cells can be reactivated to produce distinct T-helper-1 or T-helper-2 cytokine patterns, thus directing allergen-specific immunotherapy toward successful or unsuccessful outcomes. TReg cells directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. In addition, there is accumulating evidence that they may suppress IgE production and induce IgG4 and IgA production against allergens. In addition, histamine released from mast cells and basophils may efficiently contribute to immunoregulation during specific immunotherapy, and affect TReg cells and the production of their cytokines via histamine receptor 2. SUMMARY: By applying recent knowledge in TReg-cell-dependent mechanisms of peripheral tolerance, more rational and safer approaches to the prevention and cure of venom hypersensitivity may be developed in the future.     

T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells

Immune tolerance against enteric commensal bacteria is important for preventing intestinal inflammation. Deletion of phosphoinositide-dependent protein kinase 1 (Pdk1) in T?cells via Cd4-Cre induced chronic inflammation of the intestine despite the importance of PDK1 in T?cell activation. Analysis of colonic intraepithelial lymphocytes of PDK1-deficient mice revealed markedly increased CD8α(+) T?cell receptor (TCR)γδ(+) T?cells, including an interleukin-17 (IL-17)-expressing population. TCRγδ(+) T?cells were responsible for the inflammatory colitis as shown by the fact that deletion of Tcrd abolished spontaneous colitis in the PDK1-deficient mice. This dysregulation of intestinal TCRγδ(+) T?cells was attributable to a reduction in the number and functional capacity of PDK1-deficient T regulatory (Treg) cells. Adoptive transfer of wild-type Treg cells abrogated the spontaneous activation and proliferation of intestinal TCRγδ(+) T?cells observed in PDK1-deficient mice and prevented the development of colitis. Therefore, suppression of intestinal TCRγδ(+) T?cells by Treg cells maintains enteric immune tolerance.     

Is serum thioredoxin-1 a useful clinical marker for malignant pleural mesothelioma?

Malignant pleural mesothelioma (MPM), an asbestos-related aggressive malignant tumor of mesothelial origin, shows limited response to therapy and overall survival remains very poor. Reactive oxygen species play an important role in asbestos toxicity. Here, we found that the patients with MPM had significantly higher serum levels of thioredoxin-1 (TRX) than control population. The patients with advanced-stage MPM showed higher levels of TRX than those with early-stage MPM. The difference in overall survival between the groups with lower and higher serum TRX levels was significant. Our data suggest that serum TRX concentration could be a useful clinical marker for MPM.