CRELD1 modulates homeostasis of the immune system in mice and humans

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4(+) T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis. Within a human cohort, wide variation can occur with constitutively expressed proteins. Aschenbrenner and colleagues found that individuals with lower CRELD1 expression have decreased frequencies of naive CD4(+) T cells. Mice with conditional Creld1 deficiency also exhibit a phenotype associated with immunological aging.