We have shown that hypertension in response to chronic placental ischemia is associated with elevated inflammatory cytokines and CD4+ T cells. However, it is unknown if these cells play an important role in mediating hypertension in response to placental ischemia. Therefore, we hypothesize that, reduced uterine perfusion pressure, (RUPP) induced CD4+T cells increase blood pressure during pregnancy. To answer this question, CD4+T cells were isolated from spleens at day 19 of gestation from control normal pregnant and pregnant RUPP rats, cultured, adjusted to 106 cells/100µl saline for intraperitoneal injection into normal pregnant rats at day 13 of gestation. On day 18, in the experimental groups of rats, arterial catheters were inserted, and on day 19 mean arterial pressure (MAP) was analyzed. Inflammatory cytokines and anti-angiogenic factor, soluble fms-like tyrosine kinase, sFlt-1, were determined via enzyme linked immunosorbant assay. MAP increased from 104±2 mmHg in normal pregnant to 124±2 mmHg in RUPP rats (P<0.001) and to 118±1mmHg in rats receiving RUPP CD4+T cells (P<0.001). Circulating tumor necrosis factor-alpha and sFlt-1 were elevated in recipients of RUPP CD4+T cells to levels similar to control RUPP rats. In contrast, virgin rats injected with normal pregnant or RUPP CD4+T cells exhibited no blood pressure changes compared to control virgin rats. Importantly, MAP did not change in recipients of normal pregnant CD4+T cells (109 ± 3 mmHg). These data support the hypothesis that reduced uterine perfusion pressure induced CD4+ T cells play an important role in the pathophysiology of hypertension in response to placental ischemia.

Material

Human and murine MHC nonclassical class Ib-restricted invariant T (iT) cell subsets, such as invariant natural killer T cells (iNKT) and mucosal-associated invariant T cells, have specialized functions early in immune responses, especially in modulating subsequent adaptive immune responses. Here, we characterize a prominent iT population in the amphibian Xenopus laevis and show the requirement of the class Ib molecule, Xenopus nonclassical gene 10, in its differentiation and function. Using Xenopus nonclassical gene 10 tetramers and RNAi loss of function by transgenesis, we identified a large class Ib-dependent CD8 − /CD4 − iT subset in unmanipulated frogs and tadpoles. This population is critical for antiviral immunity during early larval stages when classical MHC class Ia function is suboptimal. Furthermore, in young tadpoles with low class Ia expression, deep sequencing revealed additional preponderant invariant T cell receptor (TCR)α rearrangements, implying other iT cell subsets and a predominant selection process mediated by other class Ib molecules. The restriction and requirement of class Ib molecules for development and antiviral immunity of a mammalian iNKT or mucosal-associated invariant T cell counterpart in the amphibian Xenopus show the importance of iT cells in the emergence and evolution of the adaptive immune system.

No abstract