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 wnch/wnch ) showed normal development and differentiation of major immune cell subsets in the thymus and spleen. Moreover, T cells from Cdk4 wnch/wnch mice exhibited normal cytokine production in response to in vitro stimulation. However, analysis of the mixed bone marrow chimeras revealed that Cdk4 wnch/wnch -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 wnch/wnch mutant cells are in direct competition with wild-type immune cells in the mixed bone marrow chimera.