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Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression
Justin J. Taylor, … , Markus Mohrs, Edward J. Pearce
Justin J. Taylor, … , Markus Mohrs, Edward J. Pearce
Published March 2, 2009
Citation Information: J Clin Invest. 2009;119(4):1019-1028. https://doi.org/10.1172/JCI36534.
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Research Article Infectious disease Article has an altmetric score of 1

Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression

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Abstract

Chronic infections are associated with progressively declining T cell function. Infections with helminth parasites, such as Schistosoma mansoni, are often chronic and characterized by the development of strong Th2 responses that peak during the acute stage of infection and then decline despite ongoing infection; this minimizes Th2-dependent immunopathology during the chronic stage of infection. We sought to understand the basis for the decline in Th2 responses in chronic schistosomiasis. Using IL-4 reporter mice (mice that express EGFP as a reporter for Il4 gene expression) to identify Th2 cells, we found that Th2 cell numbers plateaued during acute infection and remained constant thereafter. However, the percentages of Th2 cells proliferating during late infection were strikingly lower than those during acute infection. Th2 cell hyporesponsiveness was evident within 10 d of initiation of the Th2 response and became progressively ingrained thereafter, in response to repeated Ag stimulation. Gene expression analyses implicated the E3-ubiquitin ligase gene related to anergy in lymphocytes (GRAIL) in the hyporesponsive state. Consistent with this, suppression of GRAIL expression using retrovirally delivered siRNA prevented the development of hyporesponsiveness induced by repeated Ag stimulation in vitro or in vivo. Together, these data indicate that the decline in Th2 cell responsiveness during chronic schistosomiasis is the net result of the upregulation of GRAIL expression in response to repeated Ag stimulation.

Authors

Justin J. Taylor, Connie M. Krawczyk, Markus Mohrs, Edward J. Pearce

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Figure 3

Cell-intrinsic Th2 hyporesponsiveness is induced by repeated stimulation with antigen.

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Cell-intrinsic Th2 hyporesponsiveness is induced by repeated stimulation...
(A–F) GFP+CD4+ cells, sorted from 4get Thy1.1 mice infected with S. mansoni for 15 wk (A–C) or 7 wk (D–F), were adoptively transferred into naive (A and D), 7 wk infected (B and E), or 15 wk infected (C and F) congenic Thy1.1– recipients 1 d prior to BrdU labeling for 7 d. Proliferation of donor and recipient Th2 cells was assessed using flow cytometry to measure the incorporation of BrdU. Panels represent concatenated data from all mice within the experiment (3 mice per group). Numbers within histograms indicate mean percent BrdU+ cells. (G) Sorted GFP+CD4+ and GFP–CD4+ cells from naive, 8 wk infected, or 16 wk infected animals were restimulated in vitro with DCs pulsed with or without SEA for 72 h. Cytokine concentrations in culture supernatants were measured by ELISA. Error bars denote SD of 3 measurements per group. (H) Sorted GFP+CD4+ cells from 8 wk or 16 wk infected mice were restimulated in vitro with SEA-pulsed DCs for 72 h directly ex vivo, or for 72 h after an 8-d in vitro period during which they were continuously exposed to SEA-pulsed DCs. Numbers within histograms indicate percent BrdU+ cells.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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