Birth season and environmental influences on blood leucocyte and lymphocyte subpopulations in rural Gambian infants.

BACKGROUND: In rural Gambia, birth season predicts infection-related adult mortality, providing evidence that seasonal factors in early life may programme immune development. This study tested whether lymphocyte subpopulations assessed by automated full blood count and flow cytometry in cord blood and at 8, 16 and 52 weeks in rural Gambian infants (N = 138) are affected by birth season (DRY = Jan-Jun, harvest season, few infections; WET = Jul-Dec, hungry season, many infections), birth size or micronutrient status. RESULTS: Geometric mean cord and postnatal counts were higher in births occurring in the WET season with both season of birth and season of sampling effects. Absolute CD3+, CD8+, and CD56+ counts, were higher in WET season births, but absolute CD4+ counts were unaffected and percentage CD4+ counts were therefore lower. CD19+ counts showed no association with birth season but were associated with concurrent plasma zinc status. There were no other associations between subpopulation counts and micronutrient or anthropometric status. CONCLUSION: These results demonstrate a seasonal influence on cell counts with a disproportionate effect on CD8+ and CD56+ relative to CD4+ cells. This seasonal difference was seen in cord blood (indicating an effect in utero) and subsequent samples, and is not explained by nutritional status. These findings are consistent with the hypothesis than an early environmental exposure can programme human immune development.

Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination.

Old age is accompanied by an increased incidence of infection and poorer responses to vaccination. In this proof of principle study, old female rhesus macaques (aged 18.5 to 23.9 years) were treated with recombinant simian interleukin-7 (IL-7) or saline, according to a two-phase regime. Treatment was not associated with bone loss as judged by plasma carboxy terminal telopeptide of type I collagen (ICTP) levels, nor with neutropenia. IL-7-treated animals showed an increase in the number of blood CD4(+) CD3(+) and CD8(+) CD3(+) T cells after both phases of treatment and a transient increase in the number of naïve (CD62L(+) CD45RA(+)) T cells for both CD4(+) and CD8(+) subsets after only the first treatment. Increases in TREC levels per T cell followed both phases of treatment, but were more prolonged after the second phase. Following vaccination with inactivated influenza strain A/PR/8/34, hemagglutination inhibition assays showed that half of the IL-7-treated animals showed a greater than eight-fold increase in antibody titer following the first challenge with the vaccine. In addition IL-7-treated animals showed higher numbers of central memory CD8(+) T cells compared to pretreatment levels with numbers greater than in the saline-treated group. Animals with the highest hemagglutination inhibition titers and the best proliferation against flu antigen were among those with the highest TREC per T cell levels after the second phase of treatment. Treatment of the elderly with IL-7 may provide an effective therapy to improve the immune system.

Interleukin-7: an interleukin for rejuvenating the immune system.

Infection of an individual (aged 20-30 years) by a virus will cause a response from the T (thymus derived) lymphocytes of which there are approximately 3 x 10(11). If the individual has not met the virus before, the response will come from the naive T cell subset (50 +/- 10% of the total T cell pool at this age) containing recent thymic emigrants produced from the thymus at approximately 10(8) per day. Their antigen-specific receptor has a defined specificity governed by the conformation of its two chains (alpha and beta), and the repertoire of specificities is somewhere in the region of 2 x 10(7) to 10(8). A successful response leads to clonal expansion and the generation of memory T cells to the infecting agent.

In utero arsenic exposure is associated with impaired thymic function in newborns possibly via oxidative stress and apoptosis.

Prenatal arsenic exposure is associated with increased infant morbidity and reduced thymus size, indicating arsenic-related developmental immunotoxicity. We aimed to evaluate effects of prenatal arsenic exposure on thymic function at birth and related mechanisms of action. In a Bangladeshi cohort, arsenic was measured in urine (U-As, gestational week (GW) 8 and 30) and blood (B-As, GW14) in 130 women. Child thymic index was measured by sonography at birth and thymic function by signal-joint T-cell receptor-rearrangement excision circles (sjTRECs) in cord blood mononuclear cells (CBMC). In a subsample (n = 44), sjTRECs content in isolated CD4(+) and CD8(+) T cells, expression of oxidative-stress defense and apoptosis-related genes in CBMC, arsenic concentrations (urine, placenta, and cord blood), and oxidative stress markers in placenta and cord blood were measured. In multivariable-adjusted regression, ln U-As (GW8) was inversely associated with ln sjTRECs in CBMC (B = -0.25; 95% confidence interval [CI] -0.48 to -0.01). Using multivariable-adjusted spline regression, ln U-As (GW30) and ln B-As (GW14) were inversely associated with ln sjTRECs in CBMC (B = -0.53; 95% CI -0.93 to -0.13 and B = -1.27; 95% CI -1.89 to -0.66, respectively) below spline knots at U-As 150 µg/l and B-As 6 µg/kg. Similar inverse associations were observed in separated CD4(+) and CD8(+) T cells. Arsenic was positively associated with 8-hydroxy-2'-deoxyguanosine in cord blood (B = 0.097; 95% CI 0.05 to 0.13), which was inversely associated with sjTRECs in CD4(+) and CD8(+) T cells. In conclusion, prenatal arsenic exposure was associated with reduced thymic function, possibly via induction of oxidative stress and apoptosis, suggesting subsequent immunosuppression in childhood.

Interleukin 7 from maternal milk crosses the intestinal barrier and modulates T-cell development in offspring.

BACKGROUND: Breastfeeding protects against illnesses and death in hazardous environments, an effect partly mediated by improved immune function. One hypothesis suggests that factors within milk supplement the inadequate immune response of the offspring, but this has not been able to account for a series of observations showing that factors within maternally derived milk may supplement the development of the immune system through a direct effect on the primary lymphoid organs. In a previous human study we reported evidence suggesting a link between IL-7 in breast milk and the thymic output of infants. Here we report evidence in mice of direct action of maternally-derived IL-7 on T cell development in the offspring. METHODS AND FINDINGS: We have used recombinant IL-7 labelled with a fluorescent dye to trace the movement in live mice of IL-7 from the stomach across the gut and into the lymphoid tissues. To validate the functional ability of maternally derived IL-7 we cross fostered IL-7 knock-out mice onto normal wild type mothers. Subsets of thymocytes and populations of peripheral T cells were significantly higher than those found in knock-out mice receiving milk from IL-7 knock-out mothers. CONCLUSIONS/SIGNIFICANCE: Our study provides direct evidence that interleukin 7, a factor which is critical in the development of T lymphocytes, when maternally derived can transfer across the intestine of the offspring, increase T cell production in the thymus and support the survival of T cells in the peripheral secondary lymphoid tissue.