Production of New T Cells by Thymus in Children: Effect of HIV Infection and Antiretroviral Therapy

Abstract

The decrease in the number of CD4 ϩ T cells during HIV infection is the result of both peripheral destruction of cells by the virus and inadequate replacement of these cells. Aging and HIV infection lead to lower production of new T cells by the thymus, and, therefore, a complete restoration of the immune system is not generally achieved in infected adults after antiretroviral therapy. Because children have a completely functional thymus, we addressed the effects of HIV-1 infection on the production of new T cells in vertically infected children and whether the decrease of viral load after therapy results in a restoration of thymic function. To analyze the thymic function, T-cell receptor rearrangement excision circles were measured by quantitative PCR. Our results indicate that HIV-infected children have lower T-cell receptor rearrangement excision circle levels than age-matched uninfected children, likely due to an inhibitory effect of HIV on thymic function. Additionally, in some patients, the decrease in viral load after retroviral therapy allows the generation of new T cells by the thymus, thus recovering the normal number of CD4 cells. Depletion of CD4ϩ T cells is a hallmark of HIV infection (1). Experiments using human fetal thymus tissue implanted into SCID mice demonstrated that HIV can infect human thymocytes, leading to their death (2, 3). Therefore, the decrease in CD4 ϩ T cells in HIV-infected persons would be the result of two factors: peripheral CD4 ϩ T-cell depletion by the virus and insufficient replacement of the destroyed T cells (1).The thymus, the organ responsible for the maturation and selection of T cells, undergoes involution with age. It retains, however, a reduced ability to produce new T cells in adults (4). This thymic involution with age could be responsible for the rapid progression of HIV infection in older adults because of the difficulty of generating new T cells to replace CD4 ϩ T cells destroyed by the virus (5). In contrast, children have complete thymic function and, therefore, they have the capacity to regenerate all of the T-cell clones lost due to HIV infection, leading to a complete reconstitution of the immune system. Because T cells can have a very long life span, it is difficult to discriminate whether the "naive" T cells present in an individual are recently produced by the thymus or whether they arose from the division of cells formed in the first stages of life. Recently, Douek et al. (4) developed an assay that allows discrimination of the T cells of recent formation in the thymus from those of periphery expansion. This new assay was based on the mechanism by which the repertoire of the TCR is generated. In the genetic rearrangement of the regions V, D, and J that produce the ␣␤ TCR (6), the deletion of the TCRD locus forms some circles of DNA-denominated signal joint TREC (7,8). These circles are episomal and do not replicate during mitosis. Thus, TREC will be present only in recently produced cells by the thymus and not in those derived from the division or di...

Recovery of T‐cell subsets after antiretroviral therapy in HIV‐infected children

“…Indeed, we found a positive correlation between CD4+ CD38+ with the slope of CD4+, hence, of those three subsets in the group of children that recovered CD4 levels. Contrary to adults, in children the CD4+ CD45RA-CD62L+ subset negatively correlated with the slope of CD4, suggesting that CD4+ T-cell immune reconstitution is almost exclusively the result of an increase in naive T cells, mostly derived by new emigrants from the thymus [41], although we cannot completely rule out peripheral expansion of T cells. Despite the fact that we found a positive correlation between the slopes of percentageCD4+ and naive CD8+ T cells, we did not find significant differences between the Ns and Ps-groups.…”

“…Thus, the CD62L+ T cells cycle through the periphery lymph nodes whereas CD62L-T cells cycle through the mucosal lymphoid tissue [8]. Contrary to adults, in children the CD4+ CD45RA-CD62L+ subset negatively correlated with the slope of CD4, suggesting that CD4+ T-cell immune reconstitution is almost exclusively the result of an increase in naive T cells, mostly derived by new emigrants from the thymus [41], although we cannot completely rule out peripheral expansion of T cells. Indeed, we found a positive correlation between CD4+ CD38+ with the slope of CD4+, hence, of those three subsets in the group of children that recovered CD4 levels.…”

CD4+ T-Cell Immunodeficiency Is More Dependent on Immune Activation Than Viral Load in HIV-Infected Children on Highly Active Antiretroviral Therapy

“…thymic function. 25,26 Our results indicate that naive T-cell depletion could be likely due to immune activation status rather than HIV replication.…”

Preterm neonates show marked leukopenia and lymphopenia that are associated with increased regulatory T-cell values and diminished IL-7

“…Thymic function was studied by measuring with real-time PCR the frequency of TRECs (9,41,42) in total peripheral blood mononuclear cells or CD4 and CD8 T cells purified by immunomagnetic isolation (MiltenyiBiotec, Bergisch Gladbach, Germany). PCRs were performed in a LightCycler system using the LightCycler FastStart DNA MasterPLUS kit (Roche Molecular Biochemicals, Mannheim, Germany).…”