Immunological Phenotyping of Mice with a Point Mutation in Cdk4

Cyclin-dependent kinases (CDKs) play a crucial role in regulation of the mammalian cell cycle. CDK4 and CDK6 control the G1/S restriction checkpoint through their ability to associate with cyclin D proteins in response to growth factor signals. CDK4 deficiency in mice gives rise to a range of endocrine-specific phenotypes including diabetes, infertility, dwarfism, and atrophy of the anterior pituitary. Although CDK6 deficiency can cause thymic atrophy due to a block in the double-negative (DN) to double-positive (DP) stage of T cell development, there are no overt defects in immune cell development reported for CDK4-deficient mice. Here, we examined the impact of a novel N-ethyl-N-nitrosourea-induced point mutation in the gene encoding CDK4 on immune cell development. Mutant mice (Cdk4) showed normal development and differentiation of major immune cell subsets in the thymus and spleen. Moreover, T cells from Cdk4 mice exhibited normal cytokine production in response to in vitro stimulation. However, analysis of the mixed bone marrow chimeras revealed that Cdk4-derived T cell subsets and NK cells are at a competitive disadvantage compared to Cdk4-derived cells in the thymus and periphery of recipients. These results suggest a possible role for the CDK4^wnch mutation in the development of some immune cells, which only becomes apparent when the Cdk4 mutant cells are in direct competition with wild-type immune cells in the mixed bone marrow chimera.