Competition For Growth Factors Research Articles

Regulatory T cell Itch reins in Th2 inflammation

Regulatory T cell Itch reins in Th2 inflammation

Competition for growth factors: a lot more death with a little less Aktion

Apoptosis is frequently seen in response to cytotoxic drugs or other stimuli that provoke cell damage or stress. However, the vast majority of homeostatic cell deaths in vivo occur due to physiological cues that permit the selection of the fittest cells within a tissue, by weeding out the aged and the superfluous through competition. One such fitness test is competition for growth factors. Raff championed the idea of social control of cell death by predicting that all cells continuously require signals (i.e., growth factors) provided by other cells to maintain viability.1 The failure to compete successfully for growth factors not only prevents cell division but also can lead to the generation of signals that eliminate cells via apoptosis. However, despite the importance of this topic, it still remains unclear precisely how growth factor receptor engagement, or lack thereof, interfaces with the cell death machinery. This is also a topic of much importance because transformed cell populations frequently overexpress their own growth factors or deregulate the signaling pathways acting downstream of growth factor receptors. In addition to promoting proliferation, deregulated growth factor receptor signaling can also result in the suppression of apoptosis.2 Thus, learning how growth factor-induced pro-survival signaling operates may reveal key steps for therapeutic manipulation to enhance the sensitivity of transformed cells to chemotherapeutic drugs. So how does the failure to obtain sufficient growth factor lead to the engagement of the cell death machinery? This is the question that a paper by Ekert and colleagues,3 published in this issue of CDD, addresses.

Porcine regulatory T cells: Mechanisms and T-cell targets of suppression

Tregs are known for their suppressive capacity on various immune reactions. In swine, existence as well as suppressive activity of Foxp3 + Tregs could be demonstrated but detailed functional investigations are lacking. Therefore, we analysed the functional properties of porcine Tregs. We observed that besides TCR stimulation Tregs require IL-2 for activation. Furthermore, we investigated the following mechanisms of suppression: (i) cell–cell contact dependency, (ii) production of soluble suppressive factors and (iii) competition for growth factors. Our experiments revealed that suppression by porcine Tregs is abrogated by blocking cell–cell contact or by supplementing excessive amounts of IL-2. Additionally it could be shown that porcine Tregs produce immunosuppressive IL-10. Thereby, we demonstrated that porcine Tregs can use all main mechanisms of suppression mentioned above. Further investigations on the suppressive activity of Tregs using CFSE proliferation assays demonstrated that suppression affects T-helper cells as well as cytotoxic T lymphocytes and TCR-γδ T cells.

B-cell Tolerance

Autoreactive B cells are actively tolerized to more abundant self-antigens by a series of checkpoints involving receptor editing, deletion, anergy and competition for growth factors. In contrast, B cells reactive against rare, sequestered or tissue specific self-antigens remain functionally naïve. During an immune response, the autoimmune danger from these cells is countered by a variety of mechanisms comprising control of self-antigen presentation, limitation of immunogenic and tolerogenic costimuli including T cell help, homeostatic control of growth and strict regulation of germinal centre reactions. In this overview we consider how knowledge of these checkpoints may be used to gain a better understanding of transplant tolerance and the generation of alloantibodies.

The nature and mechanisms of DN regulatory T-Cell mediated suppression

Regulatory T cells have been reported to enhance survival of transplanted allografts. We have recently identified and cloned a novel CD3 +CD4 −CD8 − (double negative, DN) regulatory T cell from mice that were given a single class I mismatched donor lymphocyte infusion and permanently accepted donor-specific skin allografts. When infused into naïve syngeneic mice, these DN T cells prolonged the survival of class I mismatched donor skin allografts. Here we further characterize the nature and mechanism of DN T-cell mediated suppression. This present study reveals that DN T cells are able to specifically eliminate activated syngeneic CD8 + T cells that share the same T cell receptor (TCR) specificity as DN T cells in vitro. Similarly, we found that, along with an increase of recipient DN T cells in the peripheral blood, anti-donor CD8 + T cells were also eliminated in vivo following a donor lymphocyte infusion. We further demonstrate that DN T regulatory cells do not mediate suppression by competition for growth factors or antigen presenting cells (APC) nor by modulation of APC, but require cell contact with the activated target CD8 + T cells. This contact can be mediated either by the TCR on CD8 + T cells that recognize constitutively expressed or acquired MHC molecules on DN T cells, or by the TCR on DN T cells that recognize constitutively expressed MHC molecules on CD8 + T cells. Together, these data extend our previous findings, and expand the conditions in which DN T cells can potentially be used to specifically suppress allogeneic immune responses.

Glial Transplants: An in vivo Analysis of Extrinsic and Intrinsic Determinants of Dysmyelination in Genetic Variants

Myelination in the CNS depends on the ability of oligodendrocytes (Ols) to efficiently colonize the brain, differentiate, and express a precise balance of specific genes necessary for myelin synthesis. Mutations in these genes produce different types of dysmyelination in animal as in human. Defects in the synthesis of myelin constituents usually lead to mild dysmyelinations. IN contrast, mutations affecting the gene encoding the proteolipid, another major protein of myelin, produce various perturbations of Ols biology suggesting a pleiotropic effect of the gene in the development of the CNS. Studies on expansion of cell population and survival have provided contradictory information on the extrinsic and intrinsic action of the gene on Ols biology. On one hand, in vitro studies using conditioned media as in vivo studies on heterozygotes, and transplantations experiments suggest that excess of programmed cell death in these mutants is ruled out by intrinsic factors which could act during embryonic life. On the other hand, attempts to compensate the gene defect by transgenic correction demonstrate a dominant negative effect of the jp mutation on both survival and functional potential of Ols. Finally, total suppression of PLP gene expression has a restricted effect on myelin structure without excess of cell death. These contradictory results are discussed in the perspective of regulation of cell death by competition for growth factors in limiting amount. The proposed model suggests that this contradiction is only apparent, and that excess of cell death in PLP/DM20 mutant is intrinsically determined by diminished competitivity of the mutant Ols for limited amounts of environmental factors.