CD8+ T-Cell Interleukin-7 Receptor Alpha Expression as a Potential Indicator of Disease Status in HIV-Infected Children

Background: Initiation and modification of antiretroviral therapy in HIV-infected children depend on viral load and CD4+ T-cell count. However, these surrogates have limitations, and complementary immunological markers to assess therapeutic response are needed. Our aim was to evaluate CD8+ T-cell expression of CD127 as a marker of disease status in HIV-infected children, based on adult data suggesting its usefulness. We hypothesized that CD127 expression on CD8+ T-cells is lower in children with more advanced disease. Methods: In a cross-sectional evaluation, we used flow cytometry to measure CD127+ expression on CD8+ T-cells in whole blood from HIV-infected children with varying disease status. This was compared with expression of CD38 on this subset, currently used in clinical practice as a marker of disease status. Results: 51 HIV-infected children were enrolled. There was a strong positive correlation between CD127 expression on CD8+ T-cells and CD4+ T-cell count, and height and weight z-scores, and a strong negative correlation between CD127 expression and viral load. In contrast, we found no association between CD38 expression and these disease status markers. Conclusions: CD8+ T-cell CD127 expression is significantly higher in children with better HIV disease control, and may have a role as an immunologic indicator of disease status. Longitudinal studies are needed to determine the utility of this marker as a potential indicator of HIV disease progression

IL-7R expression and IL-7 signaling confer a distinct phenotype on developing human B-lineage cells

IL-7 is an important cytokine for lymphocyte differentiation. Similar to what occurs in vivo, human CD19+cells developing in human/murine xenogeneic cultures show differential expression of the IL-7 receptor α (IL-7Rα) chain (CD127). We now describe the relationship between CD127 expression/signaling and Ig gene rearrangement. In the present study, < 10% of CD19+CD127+and CD19+CD127-populations had complete VDJH rearrangements. IGH locus conformation measurements by 3D FISH revealed that CD127+and CD127-cells were less contracted than pediatric BM pro-B cells that actively rearrange the IGH locus. Complete IGH rearrangements in CD127+and CD127-cells had smaller CDR3 lengths and fewer N-nucleotide insertions than pediatric BM B-lineage cells. Despite the paucity of VDJH rearrangements, microarray analysis indicated that CD127+cells resembled large pre-B cells, which is consistent with their low level of Ig lightchain rearrangements. Unexpectedly, CD127-cells showed extensive Ig light-chain rearrangements in the absence of IGH rearrangements and resembled small pre-B cells. Neutralization of IL-7 in xenogeneic cultures led to an increase in Ig light-chain rearrangements in CD127+cells, but no change in complete IGH rearrangements. We conclude that IL-7-mediated suppression of premature Ig light-chain rearrangement is the most definitive function yet described for IL-7 in human B-cell development

Representative data from a single subject treated at 60 μg/kg/d are shown

(A) Two-dimensional plots illustrating the rhIL-7 therapy–induced increased frequency of CD4 RTEs (CD31/CD45RA; red boxes in first row of graphs), and changes in CD4 and CD8 naive, memory, and effector subsets (respectively CD45RA/CD27, CD45RA/CD27, and CD45RA/CD27 sections on second and third rows). (B) Overlay histograms of Ki-67 expression on CD4 RTEs (CD31/CD45RA) and CD4 and CD8 naive (CD45RA/CD27), memory (CD45RA/CD27), and effector (CD45RA/CD27) subsets. Percent Ki-67 cells are indicated in each frame. Red lines, pretreatment; blue lines, day 7; green lines, day 14; orange lines, day 21. Note that at the end of treatment (green line), the percentage of Ki67 memory and effector CD8 populations drop to lower levels than the naive CD8. (C) Two-dimensional plots illustrating the rhIL-7 therapy–induced changes in CD4 (top row) and CD8 (bottom row) naive, central memory, effector memory, and effectors (respectively CD45RA/CCR7, CD45RA/CCR7, CD45RA/CCR7, and CD45RA/CCR7 sections).<p><b>Copyright information:</b></p><p>Taken from "Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets"</p><p></p><p>The Journal of Experimental Medicine 2008;205(7):1701-1714.</p><p>Published online 7 Jul 2008</p><p>PMCID:PMC2442646.</p><p></p

Shown are representative images on PET-CT scan in one subject (42-yr-old female treated with 60 μg/kg/dose)

(left) Imaging on day 14 (last day of rhIL-7 treatment). (right) Day 56 (6 wk after the end of treatment). The full ovals indicate areas of increased size (except for vertebral bodies) and activity of lymphoid organs (left and right axillary adenopathy, spleen, and lumbar spine) at the end of treatment. The dotted contours indicate the thymic area where no increased activity can be demonstrated at day 14. Increased metabolic activity is seen in pink and maximal in yellow areas.<p><b>Copyright information:</b></p><p>Taken from "Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets"</p><p></p><p>The Journal of Experimental Medicine 2008;205(7):1701-1714.</p><p>Published online 7 Jul 2008</p><p>PMCID:PMC2442646.</p><p></p