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    Immunological Phenotyping of Mice with a Point Mutation in Cdk4
    (Mdpi, 2023) Yabas, Mehmet; Hoyne, Gerard F.
    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.