Naive T-cell Counts Research Articles

Shorter birth length and decreased T-cell production and function predict severe infections in children with non–severe combined immunodeficiency cartilage–hair hypoplasia

Cartilage-hair hypoplasia (CHH) is a syndromic inborn error of immunity caused by variants in the RMRP gene. Disease manifestations vary, and their ability to predict outcome is uncertain. The optimal management of infants with CHH who do not fulfill classical severe combined immunodeficiency (SCID) criteria is unknown. We described longitudinal changes in lymphocyte counts during childhood and explored correlations of early childhood clinical and laboratory features with clinical outcomes on long-term follow-up of CHH patients. Immunologic laboratory parameters, birth length, the presence of Hirschsprung disease, and severe anemia correlated to the primary end points of respiratory and severe infections. We implemented traditional statistical methods and machine learning techniques. Thirty-two children with CHH were followed up for 2.7 to 22.1 years (median, 8.2 years, in total 331.3 patient-years). None of the patients had classical SCID. Median lymphocyte subclass counts, apart from CD16+/56+ cells, were subnormal throughout childhood, but did not show age-related decline seen in healthy children. Low immunoglobulin levels were uncommon and often transient. Respiratory and/or severe infections developed in 14 children, 8 of whom had low naive T-cell counts, absent T-cell receptor excision circles, and/or partial "leaky" SCID-level lymphopenia. Shorter birth length correlated with lower lymphocyte counts and the occurrence of infections. Of the laboratory parameters, decreased naive T-cell counts and abnormal lymphocyte proliferation responses contributed most to the development of severe infections. In addition, all participants with absent T-cell receptor excision circles developed severe infections. Opportunistic infections occurred only in children with leaky SCID-level lymphopenia. Shorter birth length and a combination of laboratory abnormalities can predict the development of severe infections in children with CHH.

Ibrutinib Treatment Improves T-Cell Proliferative Ability and Effector Function in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients

Ibrutinib Treatment Improves T-Cell Proliferative Ability and Effector Function in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients

X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8+ Tcells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient Tcells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.

Modified interferon-α subtypes production and chemokine networks in the thymus during acute simian immunodeficiency virus infection, impact on thymopoiesis

Thymus dysfunction characterizes human/simian immunodeficiency virus (SIV) infections and contributes to physiopathology. However, both the mechanisms involved in thymic dysfunction and its precise timing remain unknown. We here analyzed thymic function during acute SIV infection in rhesus macaques. Rhesus macaques were intravenously infected with SIVmac251 and bled every 2/3 days or necropsied at different early time points postinfection. Naive T-cell counts were followed by flow cytometry and their T-cell receptor excision circle content evaluated by qPCR. Thymic chemokines were quantified by reverse transcription-qPCR and localized by in-situ hybridization in thymuses collected at necropsy. Thymic interferon alpha (IFN-α) subtype production was quantified by reverse transcription-qPCR combined to heteroduplex tracking assay. The effect of thymic IFN-α subtypes was tested on sorted triple negative thymocytes cultured on OP9-hDL1 cells. A reduced intrathymic proliferation history characterizes T cells produced during the first weeks of infection. Moreover, we evidenced a profound alteration of both chemokines and IFN-α subtypes transcriptional patterns in SIV-infected thymuses. Finally, we showed that IFN-α subtypes produced in the infected thymuses inhibit thymocyte proliferation, still preserving their differentiation capacity. Thymopoiesis is deeply impacted from the first days of SIV infection. Reduced thymocyte proliferation - a time-consuming process - together with modified chemokine networks is consistent with thymocyte differentiation speed-up. This may transiently enhance thymic output, thus increasing naive T-cell counts and diversity and the immune competence of the host. Nonetheless, long-lasting modification of thymic physiology may lead to thymic exhaustion, as observed in late primary HIV infection.

Impact of thymoglobulin prior to pediatric unrelated umbilical cord blood transplantation on immune reconstitution and clinical outcome

AbstractIn vivo T-cell depletion might contribute to the delayed immune reconstitution observed after unrelated umbilical cord blood transplantation (UCBT). We studied the impact of early, late, and no antithymocyte globulin (ATG) on immune reconstitution and outcome. One hundred twenty seven children receiving UCBT in London or Utrecht were divided into 3 groups: early ATG (days −9 to −5; n = 33), late ATG (days −5 to 0; n = 48), and no ATG (n = 46). The no-ATG group received mycophenolate mofetile + cyclosporin A as graft-versus-host disease (GVHD) prophylaxis, while the ATG groups received cyclosporin A + prednisone. End points studied were survival, immune recovery, infections, and GVHD. The probability of survival was similar in all groups: no ATG, 71% ± 8%; early ATG, 68% ± 9%; and late ATG, 61% ± 7%. CD3+, CD4+, and CD4+-naive T-cell counts were significantly higher (P < .001) in the no-ATG group at 1, 2, 3, 6, and 12 months post-UCBT. In the no-ATG group, significantly fewer viral reactivations (P = .021) were noted. A higher probability of severe acute GVHD (aGVHD; 31%) was found in the no-ATG group compared with 18% (P = .018) for early-ATG and 5% (P < .001) for late-ATG groups. This was not associated with more chronic GVHD (cGVHD).

Endogenous glucocorticoid receptor signaling drives rhythmic changes in human T‐cell subset numbers and the expression of the chemokine receptor CXCR4

In humans, numbers of circulating naive T cells strongly decline in the morning, which was suggested to be mediated by cortisol, inducing a CXCR4 up-regulation with a subsequent extravasation of the cells. As a systematic evaluation of this assumption is lacking, we investigated in two human placebo-controlled studies the effects of the glucocorticoid receptor (GR) antagonist mifepristone (200 mg orally at 23:00) and of suppressing endogenous cortisol with metyrapone (1 g orally at 04:00) on temporal changes in CXCR4 expression and numbers of different T-cell subsets using flow cytometry. Mifepristone attenuated, and metyrapone completely blocked, the morning increase in CXCR4 expression on naive T cells. In parallel, both substances also hindered the decline in naive T-cell numbers with this effect, however, being less apparent after mifepristone. We identified, and confirmed in additional in vitro studies, a partial agonistic GR effect of mifepristone at night (i.e., between 02:00 and 03:30) that could explain the lower antagonistic efficacy of the substance on CXCR4 expression and naive T-cell counts. CXCR4 expression emerged to be a most sensitive marker of GR signaling. Our studies jointly show that endogenous cortisol, specifically via GR activation, causes the morning increase in CXCR4 expression and the subsequent extravasation of naive T cells, thus revealing an important immunological function of the morning cortisol rise.

Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome

Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome

Vitamin A status is associated with T-cell responses in Bangladeshi men

Recommendations for vitamin A intake are based on maintaining liver stores of > or = 0.070 micromol/g, which is sufficient to maintain normal vision. We propose that higher levels may be required to maintain normal immune function. To test this hypothesis, we conducted an 8-week residential study among thirty-six healthy Bangladeshi men with low vitamin A stores. Subjects were randomised to receive vitamin A (240 mg in four doses) or placebo during study weeks 2 and 3. Vitamin A stores were estimated by isotopic dilution at week 8. Total T-cells, the naive T-cells:memory T-cells ratio and mitogen-induced lymphocyte proliferation were positively and significantly correlated with vitamin A stores (P < 0.05). Mitogen-stimulated IL-2, IL-4 and TNFalpha increased significantly (P < 0.05) in the vitamin A but not placebo group after supplementation, while IL-10 production was significantly and negatively correlated with vitamin A stores (P < 0.05). Segmented linear regression analysis revealed that naive T-cell counts and T-cell blastogenesis were positively associated with vitamin A stores above but not below 0.070 mumol/g liver. These data show that increasing vitamin A stores above the level that maintains normal vision enhances some measures of T-cell-mediated immunity, suggesting a difference in requirements for maintaining vision and immune function.

Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART

Inadequate CD4 cell count recovery despite full HIV RNA control occurs in 30% of HAART-treated HIV-infected patients. A better understanding of the relationship between T-cell dynamics and the HIV intracellular reservoir in HIV-infected patients failing to recover CD4 cell count following long-term HAART, is required. In a cross-sectional study T-cell turnover and homeostatic parameters featuring discordant responses were investigated in 27 immunologic non-responders (INR; CD4 count, < or = 200 cells/microl; HIV RNA, < or = 50 copies/ml), 15 virological non-responders (VNR; CD4 count, > or = 350 cells/microl; HIV RNA, > or = 10 000) and 22 full responders (FR; CD4 count, > or = 500 cells/microl; HIV RNA, < or = 50 copies/ml). INR displayed significantly higher activated CD38CD8 than FR (P < 0.05) and was comparable to VNR (P > 0.05). As compared with VNR and FR, INR displayed the highest level of proliferating Ki67CD4 and apoptotic CD4 cells (P < 0.05). VNR presented lower proliferation and apoptosis than FR and INR. INR displayed the lowest levels of naive T cells (P < 0.05) and a predominant memory pattern. Despite the memory/activated/apoptotic phenotype, INR showed a statistically non-significant reduction in T-cell receptor excision circles (TREC) compared to FR (P > 0.05), and substantially heightened interleukin (IL)-7 (P < 0.05), while VNR showed higher naive T-cell counts and TREC. Moreover, the reservoir of infected CD4 cells was increased in INR, with a trend toward highest intracellular HIV DNA within total, naive and memory CD4 cells. The lack of CD4 cell count recovery in INR seems to reflect a highly activated apoptotic T-cell compartment, with elevated IL-7 and thymic impairment. High levels of intracellular HIV-DNA in INR could be strictly involved in the lack of T-cell reconstitution. Immune correlates of an ultimate direction of the response to HAART, could be exploited in clinical practice for the most effective management of discordant patients, to amend immune imbalances and to improve clinical outcome.

Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease

AbstractAllogeneic hematopoietic stem cell transplantation (AHSCT) leads to a prolonged state of immunodeficiency characterized by low peripheral naive T-cell counts. To identify the mechanisms leading to this defect we quantitatively and qualitatively analyzed thymic function through quantification of T-cell receptor excision circle (TREC) frequencies (both the signal-joint TREC [sjTREC] and 6 different DβJβ TRECs, by-products of T-cell receptor [TCR] α and β gene rearrangement, respectively), in conjunction with immunophenotype and spectratype analyses in a cohort of patients sampled from 1 to 10 years following AHSCT. In this cohort, reduced thymic function was associated only with ongoing clinical chronic graft-versus-host disease (cGVHD). Nonetheless, the diversity of thymic production remained unchanged irrespective of the patient's cGVHD status. Interestingly, increased homeostatic proliferation was found in the naive T-cell compartment of cGVHD-patients who underwent transplantation. However, reduced expression of both the interleukin-7 receptor α (IL-7Rα) (CD127) chain and the antiapoptotic protein Bcl-2 was observed. Taken together, these data indicate that the inability to reconstitute the naive T-cell compartment for several years after AHSCT, in the absence of cGVHD, is a consequence of impaired naive T-cell survival rather than thymic dysfunction. (Blood. 2003;102:4600-4607)

Impaired production of naive T lymphocytes in human T-cell leukemia virus type I–infected individuals: its implications in the immunodeficient state

AbstractOpportunistic infections frequently occur in patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I) carriers. However, the underlying mechanisms of such infections remain unknown. To clarify the mechanism of immunodeficiency in those infected with HTLV-I, this study analyzed the T-cell subsets in HTLV-I carriers and patients with HTLV-I–associated myelopathy/tropical spastic paraparesis and ATL using 3-color fluorescence with CD62L and CD45RA coexpression either with CD4+ or CD8+ T cells. The number of naive T lymphocytes was markedly suppressed in patients with ATL, particularly in those with acute form, compared with uninfected control individuals. The number of naive T cells was low in HTLV-I–infected individuals under 50 years old compared with uninfected individuals, whereas the number of memory T lymphocytes was greater in HTLV-I–infected individuals. Although the increase of memory T lymphocytes correlated with HTLV-I provirus loads, no relationship was found between naive T-cell counts and provirus loads. T-cell receptor rearrangement excision circles (TRECs), which are generated by DNA recombination during early T lymphopoiesis, were quantified to evaluate thymic function in HTLV-I–infected individuals. TREC levels were lower in HTLV-I–infected individuals than in uninfected individuals. In HTLV-I carriers less than 70 years old, an increase of Epstein-Barr virus DNA in peripheral blood mononuclear cells was observed in 6 of 16 (38%) examined, whereas it was detectable in only 1 of 11 uninfected controls. These results suggested that the low number of naive T lymphocytes was due to suppressed production of T lymphocytes in the thymus, which might account for immunodeficiency observed in HTLV-I–infected individuals.

INCREASED MEMORY T-CELLS AND DECREASED NAIVE T-CELLS IN HUMAN T-CELL LEUKEMIA VIRUS INFECTED INDIVIDUALS

P040 Adult T-cell leukemia (ATL) cells are known to be of a CD45RO+ and CD45 RA- phenotype, suggesting that they represent memory T-cells. It is however yet unknown which T-cell subpopulation(s) harbors human T-cell leukemia virus (HTLV-I)-infected T-cells in individuals at the carrier state. In this study, we examined phenotypes of T-cells isolated from HTLV-I+ carriers and patients with HAM/TSP or frank ATL using the triple-color FACS analysis. The peripheral blood mononuclear cells were stained with FITC-labeled anti-CD45RA, PE-labeled anti-CD62L, and PE-Cy5-labeled anti-CD4 and -8 monoclonal antibodies, and analyzed with FACScan. In this analysis, memory T-cells were divided into three subpopulations: M1 (CDRA−, CD62L−), M2 (CD45RA−, CD62L+) and M3 (CD45RA+, CD62L−). In HTLV-I+ carriers with high provirus loads, an increase in CD4+ memory T-cells was noted in the M1 and M2 subpopulations, apparently due to an increase in HTLV-I-infected cells, while there was a profound decrease in naive T-cell counts. Naive T-cells had also decreased in a CD8+ T-cell population. The observed increase in CD4+ memory T-cells and decease in naive T-cells was apparently correlated with an increase in the provirus load. The decrease in CD4+ and CD8+ naive T-cells may account for the immunodeficiency seen in HTLV-I-infected individuals. Considering that ATL cells belong to the M1 or M2 subpopulation of memory T-cells, viral protein(s)(especially Tax) is likely to be implicated in the clonal expansion of memory T-cells, eventually resulting in leukemogenesis. Cell-type-specific action(s) of Tax and other viral regulatory proteins remains to be studied to further elucidate the leukemogenesis of ATL.

Long-Term Depletion of Naive T Cells in Patients Treated for Hodgkin's Disease

AbstractWe investigated the representation of T cells in patients who had been treated for Hodgkin's disease (HD). We found a marked depletion in both CD4 and CD8 naive T-cell counts that persists up to 30 years after completion of treatment. In contrast, CD4 and CD8 memory T-cell subsets recovered to normal or above normal levels by 5 years posttreatment. Thus, the previously-reported long-term deficit in total CD4 T-cell counts after treatment for HD is due to specific depletion of naive T cells. Similarly, total CD8 T-cell counts return to normal by 5 years only because CD8 memory T cells expand to higher than normal levels. These findings suggest that the treatment (mediastinal irradiation) results in a longterm dysregulation of T-cell subset homeostasis. The profound depletion of naive T cells may explain the altered T-cell function in treated patients, including the poor response to immunization after treatment for HD. Further, in some individuals, we identified expansions of unusual subsets expressing low levels of CD8. Eight-color fluorescence-activated cell sorting analyses showed that these cells largely express CD8αα homodimers and CD57, consistent with the phenotype of potentially extrathymically derived T cells. In addition, these cells, both CD4+ and CD4−, are probably cytotoxic lymphocytes, as they express high levels of intracellular perforin. In adults treated for HD, an increased activity of extrathymic T-cell differentiation may partially compensate for the loss of thymic-derived T cells.