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Altered lymph node composition in diphtheria toxin receptor-based mouse models to ablate dendritic cells.

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Mice engineered to express diphtheria toxin receptor (DTR) on dendritic cells (DCs) show reduced lymph node cellularity, even without toxin exposure. This suggests DTR itself impacts immune cell populations, necessitating caution in DC depletion studies.

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Area of Science:

  • Immunology
  • Cell Biology
  • Genetics

Background:

  • Dendritic cells (DCs) are crucial for regulating innate and adaptive immunity.
  • Mouse models with transgenic diphtheria toxin receptor (DTR) expression on DCs are widely used for selective DC ablation.
  • These models are assumed to have no adverse effects on immune physiology beyond toxin-induced depletion.

Purpose of the Study:

  • To investigate the unexpected effects of DTR expression on conventional DCs in mice.
  • To determine if DTR expression alone, without diphtheria toxin (DT) challenge, alters immune cell populations.
  • To assess the implications of these findings for the interpretation of DC depletion studies.

Main Methods:

  • Generation of transgenic mice with DTR expression driven by DC-restricted promoters.
  • Analysis of lymph node (LN), spleen, and nonlymphoid tissue cellularity and DC frequency.
  • Construction of mixed bone marrow chimeras to assess the dominance of the DTR phenotype.

Main Results:

  • Mice with DTR-expressed conventional DCs exhibited significant lymph node hypocellularity and reduced DC frequency.
  • These alterations were confined to LNs and not observed in spleen or nonlymphoid tissues.
  • In mixed bone marrow chimeras, the DTR-expressing DC phenotype was dominant, leading to smaller LNs and fewer DCs regardless of genetic DTR background.

Conclusions:

  • DTR expression on conventional DCs induces lymph node hypocellularity and DC paucity independently of DT administration.
  • The biological activity of DTR in mice must be considered when interpreting results from DC depletion experiments.
  • These findings highlight the need for careful consideration of genetic tools in immunological research.