No abstract

Thymectomy during early childhood is generally thought to have serious consequences for the establishment of the Tcell compartment. In the present study, we investigated the composition of the T-cell pool in the first 3 decades after thymectomy during infancy due to cardiac surgery. In the first 5 years after thymectomy, naive and total CD4 ؉ and CD8 ؉ T-cell numbers in the blood and T-cell receptor excision circle (TREC) levels in CD4 ؉ T cells were significantly lower than in healthy age-matched controls. In the first years after thymectomy, plasma IL-7 levels were significantly elevated and peripheral T-cell proliferation levels were increased by ϳ 2-fold. From 5 years after thymectomy onward, naive CD4 ؉ and CD8 ؉ T-cell counts and TRECs were within the normal range. Because TREC levels are expected to decline continuously in the absence of thymic output, we investigated whether normalization of the naive T-cell pool could be due to regeneration of thymic tissue. In the majority of individuals who had been thymectomized during infancy, thymic tissue could indeed be identified on magnetic resonance imaging scans. Whereas thymectomy has severe effects on the establishment of the naive T-cell compartment during early childhood, our data suggest that functional regrowth of thymic tissue can limit its effects in subsequent years. (Blood. 2011;118(3):627-634)

Although accumulating evidence indicates that chronic lymphocytic leukemia (CLL) is a disease with appreciable cell dynamics, it remains uncertain whether this also applies to patients with stable disease. In this study, 2 H 2 O was administered to a clinically homogeneous cohort of nine stable, untreated CLL patients. CLL dynamics in blood and bone marrow were determined and compared with normal B-cell dynamics in blood from five healthy individuals who underwent a similar 2 H 2 O labeling protocol. Average CLL turnover rates (0.08-0.35% of the clone per day) were f2-fold lower than average B-cell turnover rates from healthy individuals (0.34-0.89%), whereas the rate at which labeled CLL cells in blood disappeared (0.00-0.39% of B cells per day) was f10-fold lower compared with labeled B cells from healthy individuals (1.57-4.24% per day). Leukemic cell turnover variables inversely correlated with the level of somatic hypermutation of the CLL clone (IgVH mutations). Although CLL cells in bone marrow had a higher level of label enrichment than CLL cells in blood, no difference between proliferation rates and proapoptotic and antiapoptotic profiles of CLL cells from these compartments was observed. These data suggest that, in stable disease, there is a biological relationship between the degree of somatic hypermutation of the CLL clone and its dynamics in vivo. Furthermore, in contrast to lymph nodes, the bone marrow does not seem to be a major CLL proliferation site. [Cancer Res 2008;68(24):10137-44]

SummaryModern intensive chemotherapy for childhood haematological malignancies has led to high cure rates, but has detrimental effects on the immune system. There is little knowledge concerning long-term recovery of the adaptive immune system. Here we studied the long-term reconstitution of the adaptive immune system in 31 children treated for haematological malignancies between July 2000 and October 2006. We performed detailed phenotypical and functional analyses of the various B and T cell subpopulations until 5 years after chemotherapy. We show that recovery of newly-developed transitional B cells and naive B and T cells occurred rapidly, within months, whereas recovery of the different memory B and T cell subpopulations was slower and incomplete, even after 5 years postchemotherapy. The speed of B and T cell recovery was age-independent, despite a significant contribution of the thymus to T cell recovery. Plasmablast B cell levels remained above normal and immunoglobulin levels normalised within 1 week. Functional T cell responses were normal, even within the first year post-chemotherapy. This study shows that after intensive chemotherapy for haematological malignancies in children, numbers of several memory B and T cell subpopulations were decreased on the long term, while functional T cell responses were not compromised.

High-dose i.v. Ig (IVIg) is a prominent immunomodulatory therapy for various autoimmune and inflammatory diseases. Recent mice studies suggest that IVIg inhibits myeloid cell function by inducing a cascade of IL-33–Th2 cytokine production causing upregulation of the inhibitory FcγRIIb, as well as by modulating IFN-γ signaling. The purpose of our study was to explore whether and how these mechanisms are operational in IVIg-treated patients. We show that IVIg in patients results in increases in plasma levels of IL-33, IL-4, and IL-13 and that increments in IL-33 levels correlate with rises in plasma IL-4 and IL-13 levels. Strikingly, no upregulation of FcγRIIb expression was found, but instead a decreased expression of the activating FcγRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-γR2 subunit of the IFN-γR on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of FcγRs and IFN-γR2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-γ. Human lymph nodes and macrophages were identified as potential sources of IL-33 during IVIg treatment. Interestingly, stimulation of IL-33 production in human macrophages by IVIg was not mediated by dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN). In conclusion, high-dose IVIg treatment inhibits inflammatory responsiveness of mDCs in humans by Th2 cytokine-mediated downregulation of FcγRIIa and IFN-γR2 and not by upregulation of FcγRIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent.

It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/μl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4–9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/μl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.

Key Points C/EBPε acetylation regulates C/EBPε transcriptional activity. C/EBPε acetylation is required for neutrophil differentiation and the formation of neutrophil-specific granules.

The average lifespan of both naive and memory CD4 and CD8 T cells decreased during untreated chronic HIV-1 infection. Although the turnover of the memory T-cell populations nearly normalized during effective treatment, the turnover of naive CD4 and CD8 T cells did not seem to normalize completely.