Novel Genetic Models for Defining Immune Cell Function in Reproduction.

A wide range of immune cells and their attendant cytokine regulators are present in almost every compartment of the female reproductive tract. Various tissue remodelling, developmental and immune-regulatory functions are attributed to these cells, usually on the basis of evidence from descriptive studies and/or in vitro experiments, and often drawing on assumptions founded in knowledge of leukocyte functions in other tissue settings, which can be incomplete or inappropriate to the reproductive tract. To precisely assess and quantify the contribution of individual cytokines and immune cell lineages to reproductive processes, genetic strategies to remove or perturb individual agents provide powerful models and offer unique and sometimes unexpected insights. However, experiments in standard null mutant models are regularly confounded by influences of cytokines or leukocytes in tissue systems and processes distant to the reproductive tract, or actions earlier in development to cause embryonic or postnatal lethality, or induce compensatory adaptations that limit their utility. In part, this limitation can be overcome by using tissue-specific and / or acute gene knockout approaches, such as those offered by diptheria toxin receptor (DTR) or Cre-lox technologies. Using the Cd11b-Dtr mouse model for acute macrophage depletion, we have revealed essential and somewhat surprising roles for macrophages in early pregnany, operating principally at the level of the corpus luteum. Depletion of CD11b+ cells in the pre-implantation period causes CL demise attributable to failure of luteal vascular development and consequent impaired steroidogenic function. Ovaries from macrophage-depleted Cd11b-Dtr mice showed evidence of structural luteolysis, reduced expression of steroidogenesis genes, and infertility can be rescued by exogenous progesterone, confirming a corpus luteum defect. The same model is now proving useful for exploring how decidual macrophages contribute, in later gestation, to the events of parturition and the timing of labour. Our initial findings show that macrophage depletion on day 16.0 induces preterm birth within 48 h, accompanied by extended labour and high fetal mortality. These findings extend existing data from mice with null mutations in cytokine genes that regulate macrophage function, particularly the Csf1 (M-CSF) and Csf2 (GM-CSF) null mutant mice. Since a range of infectious, nutritional and inflammatory stressors can profoundly affect macrophage abundance and phenotypes at both a systemic and local level, it seems reasonable to predict that macrophage regulation of a range of reproductive processes is an important determinant of fertility and infertility, and that the Cd11b-Dtr and related models will yield new understanding and opportunities for intervention.