Milner, J.D., Ward, J.M., Keane-Myers, A. & Paul, W.E. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc. Natl. Acad. Sci. USA 104, 576-581

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2007; 104(2):576-81. DOI: 10.1073/pnas.0610289104
Source: PubMed


Lymphopenia and restricted T cell repertoires in humans are often associated with severe eosinophilic disease and a T cell Th2 bias. To examine the pathogenesis of this phenomenon, C57BL/6 Rag2-/- mice received limited (3 x 10(4)) or large (2 x 10(6)) numbers of CD4 T cells. Three to 5 months after transfer, mice that had received 3 x 10(4) T cells, but not those that received 2 x 10(6), developed fulminant macrophage pneumonia with eosinophilia, Ym1 deposition, and methacholine-induced airway hyperresponsiveness, as well as eosinophilic gastritis; esophagitis and other organ damage occurred in some cases. Donor cells were enriched for IL-4, IL-5, and IL-13 producers. When 3 x 10(4) cells were transferred into CD3epsilon-/- hosts, the mice developed strikingly elevated serum IgE. Prior transfer of 3 x 10(5) CD25+ CD4 T cells into Rag2-/- recipients prevented disease upon subsequent transfer of CD25- CD4 T cells, whereas 3 x 10(4) regulatory T cells (Tregs) did not, despite the fact that there were equal total numbers of Tregs in the host at the time of transfer of CD25- CD4 T cells. Limited repertoire complexity of Tregs may lead to a failure to control induction of immunopathologic responses, and limitation in repertoire complexity of conventional cells may be responsible for the Th2 phenotype.

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Available from: Andrea Keane-Myers, Jan 07, 2015
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    • "This concept, termed the "double-edged sword", was first introduced by Smith [61] in 1994, with respect to the dual role of neutrophils in viral infection. Rosenberg and Domachowske [62-64] followed with their hypothesis that eosinophils may be recruited in part to promote primary antiviral host defense, possibly in situations where acquired immune response was less than effective [65]. More specifically, through their secretory mediators, eosinophils could reduce the infectivity of RSV for target epithelial cells in vitro. "
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    ABSTRACT: There is a growing list of viruses and bacteria associated with wheezing illness and asthma. It is well known that a few of these pathogens are strongly associated with wheezing illness and asthma exacerbations. What is not known is if early childhood infections with these pathogens cause asthma, and, if so, exactly what are the pathophysiologic mechanisms behind its development. The current consensus is respiratory infection works together with allergy to produce the immune and physiologic conditions necessary for asthma diasthesis. One link between respiratory infection and asthma may be the eosinophil, a cell that plays prominently in asthma and allergy, but can also be found in the body in response to infection. In turn, the eosinophil and its associated products may be novel therapeutic targets, or at the very least used to elucidate the complex pathophysiologic pathways of asthma and other respiratory illnesses. Together or separately, they can also be used for diagnosis, treatment and monitoring. The optimal care of a patient must take into consideration not only symptoms, but also the underlying disease mechanisms.
    01/2012; 2(1):3-14. DOI:10.5415/apallergy.2012.2.1.3
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    • "− T cells separately in the two flow tubes (Lu et al., 2008; Milner et al., 2007). "
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    ABSTRACT: In this paper we compared the two methods of cell sorting (magnetic cell sorting and flow cytometry sorting) for the isolation and function analysis of mouse CD4(+) CD25(+) regulatory T (Treg) cells, in order to inform further studies in Treg cell function. We separately used magnetic cell sorting and flow cytometry sorting to identify CD4(+) CD25(+) Treg cells. After magnetic cell separation, we further used flow cytometry to analyze the purity of CD4(+) CD25(+) Treg cells, trypan blue staining to detect cell viability, and propidium iodide (PI) staining to assess the cell viability. We detected the immune inhibition of CD4(+) CD25(+) Treg cells in the in vitro proliferation experiments. The results showed that compared to flow cytometry sorting, magnetic cell sorting took more time and effort, but fewer live cells were obtained than with flow cytometry sorting. The CD4(+) CD25(+) Treg cells, however, obtained with both methods have similar immunosuppressive capacities. The result suggests that both methods can be used in isolating CD4(+) CD25(+) Treg cells, and one can select the best method according to specific needs and availability of the methodologies.
    Journal of Zhejiang University SCIENCE B 12/2009; 10(12):928-32. DOI:10.1631/jzus.B0920205 · 1.28 Impact Factor
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    • "However, conversion may diminish the severity of disease (25, 47). The inability to prevent disease may be caused by the limited T reg TCR repertoire generated by peripheral T reg cell development (Fig. S7), which has been suggested to permit autoimmunity in lymphopenic mice (48). Alternatively, it may be that peripheral conversion occurs too late to fully prevent autoimmune pathology. "
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    ABSTRACT: Although regulatory T (T reg) cells are thought to develop primarily in the thymus, the peripheral events that shape the protective T reg cell population are unclear. We analyzed the peripheral CD4(+) T cell receptor (TCR) repertoire by cellular phenotype and location in mice with a fixed TCRbeta chain. We found that T reg (Foxp3(+)) cells showed a marked skewing of TCR usage by anatomical location in a manner similar to antigen-experienced (CD44(hi)Foxp3(-)) but not naive (CD44(lo)Foxp3(-)) cells, even though CD44(hi) and T reg cells used mostly dissimilar TCRs. This was likely unrelated to peripheral conversion, which we estimate generates only a small percentage of peripheral T reg cells in adults. Conversion was readily observed, however, during the immune response induced by Foxp3(-) cells in lymphopenic hosts. Interestingly, the converted Foxp3(+) and expanded Foxp3(-) TCR repertoires were different, suggesting that generation of Foxp3(+) cells is not an automatic process upon antigen activation of Foxp3(-) T cells. Retroviral expression of these TCRs in primary monoclonal T cells confirmed that conversion did not require prior cellular conditioning. Thus, these data demonstrate that TCR specificity plays a crucial role in the process of peripheral conversion and in shaping the peripheral T reg cell population to the local antigenic landscape.
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