Adaptive immunity is dispensable for appendage regeneration in highly regenerative vertebrates

Adaptive immunity has been implicated in tissue repair and homeostasis, however its requirement for complex appendage regeneration in adult vertebrates remains unknown. Here, we show that adaptive immune components are dynamically recruited to regenerating appendages. Using genetic lymphocyte ablation in highly regenerative vertebrates, axolotl (Ambystoma mexicanum) and zebrafish (Danio rerio), we show that mature T and B cells are dispensable for limb, tail and fin regeneration in sexually mature animals. Despite depletion of peripheral and lymphoid T and B populations, Rag1-/- axolotls and zebrafish regenerate appendages with normal kinetics, patterning, and skeletal outcomes. Rag1 -/- regenerating blastemas undergo transcriptomic remodelling including alterations in innate immune and extracellular matrix remodelling genes, accompanied by enhanced neutrophil/myeloid infiltration, highlighting innate immunity as a potential compensatory element for regenerative success. Together, these results indicate that adaptive immunity is not required for restoration of complex appendages in vertebrates, a finding of basic and translational relevance. HighlightsO_LIRag1-/- axolotls lack mature T and B cells in lymphoid organs and periphery. C_LIO_LIRag1-/- axolotls and zebrafish regenerate appendages with kinetics, patterning and sizes comparable to wild-type siblings. C_LIO_LIRag1-/- blastemas show downregulation of adaptive immune programs, modulation of innate immune genes, and heightened myeloid activity and/or infiltration in Rag1-/- animals. C_LIO_LIInnate immune compensation likely enables functional regeneration in the absence of mature adaptive lymphocytes. C_LI