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Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency.

Lang PA, Shaabani N, Borkens S, Honke N, Scheu S, Booth S, Brenner D, Meryk A, Barthuber C, Recher M, Mak TW, Ohashi PS, Häussinger D, Griffiths GM, Thrasher AJ, Bouma G, Lang KS - J. Allergy Clin. Immunol. (2012)

Bottom Line: Despite a significant proportion of patients with WAS having recurrent viral infections, surprisingly little is known about the effects of WASP deficiency on antiviral immunity.IFN-I production by WAS KO DCs was reduced both in vivo and in vitro.These findings might help us to understand the immunodeficiency of WAS.

View Article: PubMed Central - PubMed

Affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

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Related in: MedlinePlus

Impaired CD8+ T-cell response in patients with WASP deficiency. The virus-specific CD8+ T-cell response was analyzed after LCMV infection as the total number of CD8+ T cells (left panel) or the number of LCMV-specific, GP33-tetramer–positive CD8+ T cells (right panel) in the spleen (A), liver (B), and blood (C). IL-7R expression was determined on virus-specific CD8+ T cells (D). IFN-γ expression was analyzed by using FACS after restimulation of in vivo–primed (day 6) virus-specific T cells (E). Swelling of the footpad after LCMV infection was analyzed over time (F). Cytotoxicity of CD8+ T cells was determined in virus-specific (F) and allogeneic (G) settings. Data are shown as means ± SEMs in Fig 3, A to C, and represent 4 to 8 mice (C57BL/6 mice: day 6, n = 5-6; day 12, n = 7-8; day 20, n = 4-5; WAS KO mice: day 6, n = 6; day 12, n = 6; day 20, n = 4); Fig 3, D, n = 3, representative of at least 2 independent experiments; Fig 3, E, n = 5 to 6; Fig 3, F, n = 6 to 8; Fig 3, G, n = 6; and Fig 3, H, is a representative experiment of 2 independent experiments with a total of n = 4.
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fig3: Impaired CD8+ T-cell response in patients with WASP deficiency. The virus-specific CD8+ T-cell response was analyzed after LCMV infection as the total number of CD8+ T cells (left panel) or the number of LCMV-specific, GP33-tetramer–positive CD8+ T cells (right panel) in the spleen (A), liver (B), and blood (C). IL-7R expression was determined on virus-specific CD8+ T cells (D). IFN-γ expression was analyzed by using FACS after restimulation of in vivo–primed (day 6) virus-specific T cells (E). Swelling of the footpad after LCMV infection was analyzed over time (F). Cytotoxicity of CD8+ T cells was determined in virus-specific (F) and allogeneic (G) settings. Data are shown as means ± SEMs in Fig 3, A to C, and represent 4 to 8 mice (C57BL/6 mice: day 6, n = 5-6; day 12, n = 7-8; day 20, n = 4-5; WAS KO mice: day 6, n = 6; day 12, n = 6; day 20, n = 4); Fig 3, D, n = 3, representative of at least 2 independent experiments; Fig 3, E, n = 5 to 6; Fig 3, F, n = 6 to 8; Fig 3, G, n = 6; and Fig 3, H, is a representative experiment of 2 independent experiments with a total of n = 4.

Mentions: To analyze the CD8+ response in vivo in more detail, we infected wild-type C57BL/6 or WAS KO mice with LCMV and analyzed the virus-specific CD8+ T-cell response. Six days after infection, the total number of CD8+ T cells and LCMV-specific, GP33 tetramer–positive CD8+ T cells in the spleen, liver, and blood was similar between C57BL/6 and WAS KO mice (Fig 3, A-C). However, on days 12 and 20 after infection, the numbers of total and virus-specific CD8+ T cells recovered from blood was markedly reduced in WAS KO mice (Fig 3, C), whereas at that time, LCMV had been eliminated in C57BL/6 mice (Fig 1, C). WAS KO mice also mounted CD8+ T-cell responses specific for the immunodominant epitope of the LCMV nucleoprotein (NP396), but although reduced compared with values seen in C57BL/6 mice, this did not reach statistical significance (see Fig E1 in this article's Online Repository at www.jacionline.org). A typical CD8+ T-cell response will peak around day 8 after infection, after which only a small subset of CD8+ T cells will survive and develop into memory T cells. This subset can be identified by IL-7 receptor (IL-7R) expression.39,41,42


Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency.

Lang PA, Shaabani N, Borkens S, Honke N, Scheu S, Booth S, Brenner D, Meryk A, Barthuber C, Recher M, Mak TW, Ohashi PS, Häussinger D, Griffiths GM, Thrasher AJ, Bouma G, Lang KS - J. Allergy Clin. Immunol. (2012)

Impaired CD8+ T-cell response in patients with WASP deficiency. The virus-specific CD8+ T-cell response was analyzed after LCMV infection as the total number of CD8+ T cells (left panel) or the number of LCMV-specific, GP33-tetramer–positive CD8+ T cells (right panel) in the spleen (A), liver (B), and blood (C). IL-7R expression was determined on virus-specific CD8+ T cells (D). IFN-γ expression was analyzed by using FACS after restimulation of in vivo–primed (day 6) virus-specific T cells (E). Swelling of the footpad after LCMV infection was analyzed over time (F). Cytotoxicity of CD8+ T cells was determined in virus-specific (F) and allogeneic (G) settings. Data are shown as means ± SEMs in Fig 3, A to C, and represent 4 to 8 mice (C57BL/6 mice: day 6, n = 5-6; day 12, n = 7-8; day 20, n = 4-5; WAS KO mice: day 6, n = 6; day 12, n = 6; day 20, n = 4); Fig 3, D, n = 3, representative of at least 2 independent experiments; Fig 3, E, n = 5 to 6; Fig 3, F, n = 6 to 8; Fig 3, G, n = 6; and Fig 3, H, is a representative experiment of 2 independent experiments with a total of n = 4.
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fig3: Impaired CD8+ T-cell response in patients with WASP deficiency. The virus-specific CD8+ T-cell response was analyzed after LCMV infection as the total number of CD8+ T cells (left panel) or the number of LCMV-specific, GP33-tetramer–positive CD8+ T cells (right panel) in the spleen (A), liver (B), and blood (C). IL-7R expression was determined on virus-specific CD8+ T cells (D). IFN-γ expression was analyzed by using FACS after restimulation of in vivo–primed (day 6) virus-specific T cells (E). Swelling of the footpad after LCMV infection was analyzed over time (F). Cytotoxicity of CD8+ T cells was determined in virus-specific (F) and allogeneic (G) settings. Data are shown as means ± SEMs in Fig 3, A to C, and represent 4 to 8 mice (C57BL/6 mice: day 6, n = 5-6; day 12, n = 7-8; day 20, n = 4-5; WAS KO mice: day 6, n = 6; day 12, n = 6; day 20, n = 4); Fig 3, D, n = 3, representative of at least 2 independent experiments; Fig 3, E, n = 5 to 6; Fig 3, F, n = 6 to 8; Fig 3, G, n = 6; and Fig 3, H, is a representative experiment of 2 independent experiments with a total of n = 4.
Mentions: To analyze the CD8+ response in vivo in more detail, we infected wild-type C57BL/6 or WAS KO mice with LCMV and analyzed the virus-specific CD8+ T-cell response. Six days after infection, the total number of CD8+ T cells and LCMV-specific, GP33 tetramer–positive CD8+ T cells in the spleen, liver, and blood was similar between C57BL/6 and WAS KO mice (Fig 3, A-C). However, on days 12 and 20 after infection, the numbers of total and virus-specific CD8+ T cells recovered from blood was markedly reduced in WAS KO mice (Fig 3, C), whereas at that time, LCMV had been eliminated in C57BL/6 mice (Fig 1, C). WAS KO mice also mounted CD8+ T-cell responses specific for the immunodominant epitope of the LCMV nucleoprotein (NP396), but although reduced compared with values seen in C57BL/6 mice, this did not reach statistical significance (see Fig E1 in this article's Online Repository at www.jacionline.org). A typical CD8+ T-cell response will peak around day 8 after infection, after which only a small subset of CD8+ T cells will survive and develop into memory T cells. This subset can be identified by IL-7 receptor (IL-7R) expression.39,41,42

Bottom Line: Despite a significant proportion of patients with WAS having recurrent viral infections, surprisingly little is known about the effects of WASP deficiency on antiviral immunity.IFN-I production by WAS KO DCs was reduced both in vivo and in vitro.These findings might help us to understand the immunodeficiency of WAS.

View Article: PubMed Central - PubMed

Affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Show MeSH
Related in: MedlinePlus