This study shows that, in humans at birth, circulating T cells represent recent thymic emigrants (RTEs) as reflected in their high level of expression of TCR excision circles. RTEs express “thymocyte-like” characteristics with regard to rapid rate of apoptosis. In the presence of common γ-chain cytokines, in particular IL-7, they show enhanced potential to survive, entry into cell cycle, and proliferation. Although common γ-chain cytokines were also potent antiapoptotic stimuli for mature adult-derived naive CD4+CD45RA+ T cells, these cells were refractory to IL-7-induced expansion in vitro. RTEs cultured with IL-7 could not reinduce recombination-activating gene-2 gene expression in vitro. These data suggest that postthymic naive T cells in the periphery during early life are at a unique stage in ontogeny as RTEs, during which they can undergo homeostatic regulation including expansion and survival in an Ag-independent manner while maintaining their preselected TCR repertoire.

No abstract

This study examines the influence of IL-7 on post-thymic CD4+ T cells using cord blood as a model system. Survival of naive cord blood T cells in the presence of IL-7 alone was significantly prolonged by up-regulating bcl-2, thereby preventing apoptosis while maintaining maximal cell viability. Cultures without IL-7 showed high rates of apoptosis resulting in 50% cell death by day 5 of culture. Upon phorbol 12-myristate 13-acetate + ionomycin stimulation, accumulation of cytoplasmic IL-2 was similar to that observed in freshly isolated cells, but no IL-4- or IFN-gamma-positive cells were detected. IL-7 maintained the naive T cells in a quiescent state expressing the CD45RA antigen. A significant finding was the loss of CD38 antigen expression on the naive cord blood T cells to levels similar to that observed on adult naive T cells. In contrast to the reduced proliferative response of fresh cord blood T cells to anti-CD2 + CD28 stimulation, the proliferative response of IL-7-treated cells was similar to that of adult naive T cells. This study shows that as well as maintaining the naive T cell pool by enhancing cell survival and up-regulating bcl-2 expression, IL-7 also functions as a maturation factor for post-thymic naive T cells.

Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is associated with an accelerated course of HCV infection and a faster progression to severe liver disease. We have investigated whether the development of liver disease in coinfected patients is associated with specific chemokine and cytokine production. Four cohorts--HCV/HIV-coinfected patients, HCV-monoinfected patients, HIV-monoinfected patients, and healthy control subjects--were studied. Serum levels of the 10-kDa interferon- gamma -inducible protein (IP-10) were higher in all 3 groups of infected patients than in control subjects (P<.0001). HCV/HIV-coinfected patients had significantly higher IP-10 levels than monoinfected patients. In HCV-monoinfected patients, liver fibrosis scores and liver enzyme levels were positively correlated with IP-10 levels. Elevated IP-10 levels are associated with and may contribute to liver damage in both HCV-monoinfected and HCV/HIV-coinfected patients.

SUMMARYHighly purified CD4+ CD45RA+ cells from cord blood and peripheral blood from healthy adults were studied. The levels of expression of the CD2, CD3, CD4 and CD28 antigens were similar; however, CD45 and CD45RA antigen expression were slightly lower in cord cells. The reduced expression of the CD45RA antigen on cord CD4+ T cells was confirmed in whole blood. Functional assessment revealed deficiencies in cord CD4+ CD45RA+ T cells. Interleukin-2 (IL-2) production in response to specific triggering via CD2 monoclonal antibody (mAb) alone, or CD2 mAb in combination with CD28 mAb showed marked underproduction (about 10% of adult production). When CD25 expression was examined, it was observed that the proportion of activated CD4+ CD45RA+ T cells in cord blood was lower than in adult (about 20% of adult expression). Proliferation to CD2 mAbs or CD2+28 mAbs of cord blood naive cells was similarly depressed. Investigation of IL-2 mRNA expression under these stimulatory conditions paralleled the results observed for CD25 expression, IL-2 production and proliferation. When phorbol 12-myristate 13-acetate (PMA) was added to the cells triggered with CD2+28mAbs, the responses examined were enhanced in both cord and adult blood with no significant differences between the groups. These findings suggest that under identical conditions of stimulation, purified cord blood CD4+ CD45RA+ T cells do not acquire similar activation status as their adult counterparts. These finding may help in understanding the reduced graft-versus-host disease (GVHD) observed in cord blood stem cell transplantation.

Human cytomegalovirus (HCMV) strains may be genotyped based on polymorphisms that exist within the UL144 gene, which is one of 19 viral genes lost in attenuated laboratory strains. In the present study, UL144 genotypes in congenitally infected babies (congenital cytomegalovirus [cCMV]) were determined, and the relationship between the genotype, viral load, cytokine profile, and patient developmental outcome was investigated. All cCMV infections identified during 2006 and 2007 were included (n ‫؍‬ 29). A portion of the infants were clinically assessed at birth and at 12 to 18 months postinfection for cCMV clinical sequelae (n ‫؍‬ 18/29). The plasma viral load (PVL) was requested for 23/29 patients, and the UL144 genotype was determined (n ‫؍‬ 27/29). The cytokine profile in patient plasma or serum was assessed (n ‫؍‬ 20/29). UL144 genotypes A, B, and C were detected within the cCMV population at 33.3%, 29.6%, and 25.9%, respectively. UL144 A and C were associated with a high PVL (P < 0.04). Furthermore, a significant association between the developmental outcome and UL144 A and C was observed (P < 0.04). Only patients infected with UL144 B and A/B were described as having a normal clinical outcome. In addition, a significant correlation between interleukin 10 (IL-10) levels and the PVL was observed (P < 0.04); however, there was no association between the genotype and the cytokine profile. The present study determined that the specific detection of UL144 genotypes A and C was indicative of serious cCMV infection and more likely to lead to long-term cCMV-associated clinical manifestations. The inclusion of HCMV UL144 genotyping along with the recommended PVL monitoring following cCMV diagnosis may aid prediction of the clinical outcome.

We observed a strong bias for acute mumps virus infection in males compared to females (P < 10 ؊32 ) that was independent of vaccination status.

SUMMARYClinical evidence has indicated that the neonatal cell-mediated immune response to primary infection is delayed when compared to that of adults with the same primary infection. The mechanisms regulating the development of antigen-specific T-cell immunity in neonates remain to be elucidated. We examined the primary immune response to the non-recall antigen, keyhole limpet haemocyanin (KLH) in adults and neonates in vitro. We report here that conventional bulk culture methods show reduced proliferative responses in neonates although statistical significance was not achieved. Using limiting dilution analysis, the frequencies of KLH-specific T lymphocytes were 10-100-fold lower in neonates when compared to adults. Interleukin-2 (IL-2) production was significantly lower in the supernatants of neonatal mononuclear cells (MNC) stimulated with KLH when compared to adults. Addition of exogenous IL-2 increased precursor frequencies twofold in both adult and newborn cultures. In contrast to the secreted IL-2 levels, IL-2 mRNA expression was higher in antigen-stimulated neonatal MNC preparations, even though proliferation was lower. These observations indicate differential in vitro responsiveness in neonates and adults to primary antigenic challenge. Since no IL-2 was detected in cell lysates, the presence of high levels of IL-2 mRNA and low IL-2 production suggests inability by neonatal MNC to translate IL-2. This deficiency in IL-2 production may explain the reduced precursor frequencies, suggesting failure to recruit T lymphocytes in order to expand the KLH-specific T-cell response. These observations are important for the understanding of the development of primary immune responses and immunological maturation in neonates.