Cernunnos Deficiency Reduces Thymocyte Life Span and Alters the T Cell Repertoire in Mice and Humans

Cernunnos is a DNA repair factor of the nonhomologous end-joining machinery. Its deficiency in humans causes radiosensitive severe combined immune deficiency (SCID) with microcephaly, characterized in part by a profound lymphopenia. In contrast to the human condition, the immune system of Cernunnos knockout (KO)mice is not overwhelmingly affected. In particular, Cer-nunnos is dispensable during V(D)J recombination in lymphoid cells. Nevertheless, the viability of thymocytes is reduced in Cernunnos KOmice, owing to the chronic activation of a P53-dependent DNA damage response. This translates into a qualita-tive alteration of the T cell repertoire to one in which the most distal V and J segments are missing. This results in the contrac-tion of discrete T cell populations, such as invariant natural killer T (iNKT) andmucosa-associated invariant T (MAIT) cells, in both humans andmice. The immune system is the site of intense genome dynamics, inparticular during the development andmaturation of B and T lymphocytes in bone marrow and the thymus, when antigen re-ceptor genes are rearranged through V(D)J recombination prior to their expression. DNA damages are also likely to occur during the several phases of intense proliferation which accompany the development of B and T cells. V(D)J recombination is the prototypical example of the gen