Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression
Justin J. Taylor, Connie M. Krawczyk, Markus Mohrs, Edward J. Pearce
Justin J. Taylor, Connie M. Krawczyk, Markus Mohrs, Edward J. Pearce
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Research Article Infectious disease

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

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 1

The Th2 population is maintained but hyporesponsive during chronic schistosome infection.

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The Th2 population is maintained but hyporesponsive during chronic schis...
(A) At 3, 6, 8, and 16 wk after infection, CD4+ splenocytes from control uninfected 4get mice, as well as mice infected with S. mansoni for the indicate times, were analyzed ex vivo for the expression of IL-4/GFP by flow cytometry. Numbers within plots indicate mean ± SD percent CD4+ cells that are IL-4/GFP+ (3–5 mice per group). (B) Total number of Th2 cells in the spleen, determined using the percentages measured by flow cytometry coupled with spleen cell numbers ascertained by counting. Data points are from individual mice from 6 independent experiments; horizontal lines indicate mean values. (C) BrdU incorporation into gated GFP+CD4+ cells in the spleens of naive control mice, as well as mice infected with S. mansoni for the indicated times, was assessed ex vivo following a 7-d labeling period in vivo. Numbers within histograms indicate mean percent BrdU+ cells (3–4 mice per group). (D) Same as in C, except Ki-67 expression was analyzed in addition to BrdU incorporation after a 5-d BrdU labeling period in vivo. Numbers within plots indicate percent cells in the respective quadrants. Bold numbers indicate mean percent Ki-67+ cells (3–4 mice per group). Plots and quadrant statistics are from representative animals.