Alterations in thymopoiesis in intact and peripubertally orchidectomized adult rats of different age.

In adult rats 3, 6 and 9 months post-orchidectomy performed at the age of 30 days the thymus weight, thymocyte yield and relative proportions of thymocyte subsets (delineated by expression of CD4/CD8 molecules and TCRalphabeta) were analyzed in order to elucidate a putative role of male gonadal hormones in the shaping of thymus size and intrathymic T cell maturation. In 4-month-old control rats the thymus size and cellularity returned to the corresponding levels in 1-month-old rats. These levels were sustained during the following 6 months. In spite of that, the distribution of the main thymocyte subsets in these rats was subjected to significant changes, probably due to an age-associated diminishing thymus ability to provide efficient T cell differentiation. The results added further weight to a potential feedback regulatory role of CD4+8- cells in thymopoiesis. Furthermore, they revealed that the orchidectomy-induced (i) enlargement of the thymus size and enrichment of the thymic lymphoid cell content are of a limited duration; and (ii) alterations in the relative proportion of thymocytes become quantitatively more pronounced with duration of the gonadal deprivation. Thus, the study also indicates that the age-associated changes in gonadal hormones may be, at least partly, responsible for the age-related reshaping of the T cell maturation sequence, and hence for remodeling T cell dependent immune functions.

Pregnancy does not deter the development of a potent maternal protective CD8+ T-cell acquired immune response against Listeria monocytogenes despite preferential placental colonization.

PROBLEM: Listeria monocytogenes (LM) preferentially colonizes the placenta and causes fetal loss and systemic disease during pregnancy. As systemic CD8+ T-cell memory is critical in controlling LM infection, we addressed the issue as to whether it is modulated during pregnancy. METHOD OF STUDY: Pregnant mice were infected with LM and their immune response was quantified relative to the non-pregnant cohort using advanced immunological techniques. RESULTS: Pregnant mice exhibited progressive and massive placental LM infection leading to fetal resorptions. In contrast, they harbored significantly lower bacteria in spleen and liver relative to non-pregnant controls, and rapidly cleared systemic infection. Both pregnant and non-pregnant mice exhibited similar activation of systemic innate immunity. Moreover, LM infection in pregnant and non-pregnant hosts evoked strong antigen-specific cytolytic CD8+ T cells that produced IFN-gamma. Consequently, LM infection initiated during pregnancy afforded long-term protective memory to secondary infection. CONCLUSION: Maternal hosts generate a normal Listeria-specific adaptive immunity in particular CD8+ T-cell memory response suggesting that systemic listeriosis during pregnancy may be an immunopathology associated with placental infection.

Pregnancy impairs the innate immune resistance to Salmonella typhimurium leading to rapid fatal infection.

Typhoid fever and gastroenteritis caused by Salmonella enterica species are increasing globally. Pregnancy poses a high risk, but it is unclear how maternal immunity to infection is altered. In mice, susceptible strains die of S. enterica serovar typhimurium (ST) infection within 7 days whereas resistant mice (129 x 1/SvJ) develop a chronic infection. We found that virulent ST infection during pregnancy, in normally resistant 129 x 1/SvJ mice, evoked approximately 100% fetal loss and surprisingly >60% host fatality, with a median survival of 6 days. Splenic bacterial load was 1000-fold higher in pregnant mice. This correlated to a diminished splenic recruitment/expansion of innate immune cells: dendritic cells, neutrophils, and NK cells. In particular, the splenic expansion and activation of NK cells postinfection seen in nonpregnant mice was lacking in pregnancy. Most notably, pregnant-infected mice had decreased production of serum IL-12 and increased IL-6 levels. Moreover, uteroplacental tissue of pregnant-infected mice exhibited an approximately 40-fold increase in IL-6 mRNA expression relative to noninfected placenta, whereas IL-12p40 was not increased. In vivo blocking of IL-6 significantly reduced the splenic bacterial burden in pregnant mice yet failed to prevent fetal loss. Fetal demise correlated to the rapidity of infection; by 14 h, ST expanded to >10(5) in the placenta and had reached the fetus. Therefore, the preferential placental expansion of ST plausibly altered the inflammatory response toward IL-6 and away from IL-12, reducing the recruitment/activation of splenic innate immune cells. Thus, highly virulent pathogens may use placental invasion to alter systemic host resistance to infection.

Neonatal androgenization affects the intrathymic T-cell maturation in rats.

The thymus structure, expression of CD4/CD8/TCRalphabeta on thymocytes and thymocyte proliferative and apoptotic indexes were analyzed in sexually immature 30-day-old and in sexually mature 60-day-old female rats neonatally androgenized (NA) by subcutaneous injection of 500 microg testosterone propionate/day on days 1-3 and in their vehicle-administered counterparts. The treatment affected normal thymus development. Thus, at 30 days of age, there was a reduction in the thymus weight, reflecting a decrease in the main thymic compartments. However, at 60 days of age, thymus weight did not significantly differ from that in age-matched controls, since the cortical volume enlargement was followed by a proportional decrease in the medullary volume. In rats of both ages, the changes in thymic compartments most likely reflected alterations in the size of both lymphoid and nonlymphoid components. Furthermore, in NA rats, substantial changes in thymocyte phenotypic characteristics were registered, in spite of their age. In both groups of NA rats, a decrease in the relative proportion of the least mature CD4-8-TCRalphabeta- cells and in that of CD4+8- TCRalphabeta-/TCRalphabeta(low) cells followed by an increase in the percentage of their successor CD4+8+TCRalphabeta-/TCRalphabeta(low) cells was detected. In addition, in 30-day-old NA rats, the relative proportions of CD4+8+TCRalphabeta(high) cells (just positively selected) and that of mature single positive (CD4+8- and CD4-8+) and CD4-8- double negative TCRalphabeta(high) cells, were reduced, while in 60-day-old NA rats only the percentage of CD4+8+TCRalphabeta(high) thymocytes was decreased. Thus, the study showed that the changes in the development of the hypothalamo-pituitary-gonadal axis induced by neonatal androgenization may affect the thymus development and intrathymic T-cell maturation.