CD11c depletion severely disrupts Th2 induction and development in vivo - PubMed (original) (raw)

CD11c depletion severely disrupts Th2 induction and development in vivo

Alexander T Phythian-Adams et al. J Exp Med. 2010.

Abstract

Although dendritic cells (DCs) are adept initiators of CD4(+) T cell responses, their fundamental importance in this regard in Th2 settings remains to be demonstrated. We have used CD11c-diphtheria toxin (DTx) receptor mice to deplete CD11c(+) cells during the priming stage of the CD4(+) Th2 response against the parasitic helminth Schistosoma mansoni. DTx treatment significantly depleted CD11c(+) DCs from all tissues tested, with 70-80% efficacy. Even this incomplete depletion resulted in dramatically impaired CD4(+) T cell production of Th2 cytokines, altering the balance of the immune response and causing a shift toward IFN-γ production. In contrast, basophil depletion using Mar-1 antibody had no measurable effect on Th2 induction in this system. These data underline the vital role that CD11c(+) antigen-presenting cells can play in orchestrating Th2 development against helminth infection in vivo, a response that is ordinarily balanced so as to prevent the potentially damaging production of inflammatory cytokines.

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Figures

Figure 1.

Figure 1.

CD11c, not basophil, depletion disrupts Th2 induction in schistosome egg-challenged mice. CD11c.DOG x 4get mice were treated daily with PBS (squares) or DTx (triangles) from day −2 to 6. On day −1, 1, and 3 mice were also treated with IgG (black symbols) or Mar-1 (gray symbols). On day 0, mice were challenged with S. mansoni eggs or PBS. pLN CD11cHiMHCII+ cell depletion was assessed on day 7 (A and B), and IL-4-eGFP+B220−CD4−CCR3−CD117− basophil depletion in the blood on day 4 (C and D), after egg injection. On day 7, pLN cells from naive or egg-injected, PBS (white or black bars) or DTx (gray bars), IgG or Mar-1–treated mice were cultured for 72 h with SEA or medium alone. The supernatants were collected, and SEA-specific cytokine production (medium alone values subtracted) was assessed by ELISA (E and F). pLN cells were also assessed on day 7 for IL-4-eGFP expression (G and H). One of three experiments. Error bars are mean ± SEM of four to seven mice/group.

Figure 2.

Figure 2.

CD11c depletion compromises Th2 induction and development during schistosome infection. CD11c.DOG mice were treated daily with PBS (squares) or DTx (triangles) from day 28 to 39 of S. mansoni infection. Naive (black symbols) and infected (gray symbols) mice were assessed for splenic CD11cHiMHCII+ cell depletion on day 40 (A and B) and splenocytes (C and D) from naive or infected PBS (white or black bars)- or DTx (gray bars)-treated mice, or purified CD4+ T cells and irradiated splenocytes (E and F), were cultured for 72 h with SEA or medium alone. The supernatants were collected, and cytokine production was assessed by ELISA. Splenic CD4+ T cell IL-4 production by naive (black symbols) or infected (gray symbols) mice was also assessed by intracellular cytokine staining (G and H). One out of six (A and B), three (C and D), or two (E–H) experiments. Error bars are mean ± SEM of four to seven mice/group (B and H) or SEA-specific cytokine production (medium alone values subtracted) by 4 to 7 naive or infected mice/group (C and D) or 6 technical replicates for each group of pooled purified CD4+ T cells from infected mice, cultured in medium or SEA (E and F).

Figure 3.

Figure 3.

CD11c depletion during schistosome infection impairs the liver Th2 response. CD11c.DOG mice were treated daily with PBS (squares) or DTx (triangles) from day 28 to 39 of S. mansoni infection. Naive (black symbols) and infected (gray symbols) mice were assessed for liver CD11cHiMHCII+ cell depletion on day 40 (A and B), and liver cells from naive or infected PBS (white or black bars)- or DTx (gray bars)-treated mice cultured for 72 h with SEA or medium alone. The supernatants were collected, and cytokine production was assessed by ELISA (C and D). Liver CD4+ T cell IL-4 production by naive (black symbols) or infected (gray symbols) mice was also assessed by intracellular cytokine staining (E and F). One of three (A and C–F) experiments, or combined data from three experiments (B). Error bars are mean ± SEM of four to seven mice/group, with liver cells combined in groups where cell numbers were restrictive.

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