Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes

Although the relative contribution of different immune effector functions to clearing tissues of cytomegalovirus is controversial, the contribution of CD8+ T lymphocytes has generally been accepted as essential. In this report, we show that under certain conditions the CD8+ T-lymphocyte subset can be dispensable for clearance of cytomegalovirus. Mice depleted of the CD8+ T-lymphocyte subset eliminated infectious virus with a clearance kinetics similar to that of normal mice. Adoptive transfer studies revealed that the limitation of virus spread required the cooperation between the CD4+ subset and other cells. Comparison between protective functions generated in fully immunocompetent and in CD8- mice demonstrated that elimination of the CD8+ subset before infection altered the quality of the antiviral immune response. The compensatory protective activity gained by CD4+ cells in CD8- mice was absent in normal mice recovering from virus infection

Early Interferon-γ Production in Human Lymphocyte Subsets in Response to Nontyphoidal Salmonella Demonstrates Inherent Capacity in Innate Cells

Background Nontyphoidal Salmonellae frequently cause life-threatening bacteremia in sub-Saharan Africa. Young children and HIV-infected adults are particularly susceptible. High case-fatality rates and increasing antibiotic resistance require new approaches to the management of this disease. Impaired cellular immunity caused by defects in the T helper 1 pathway lead to intracellular disease with Salmonella that can be countered by IFNγ administration. This report identifies the lymphocyte subsets that produce IFNγ early in Salmonella infection. Methodology Intracellular cytokine staining was used to identify IFNγ production in blood lymphocyte subsets of ten healthy adults with antibodies to Salmonella (as evidence of immunity to Salmonella), in response to stimulation with live and heat-killed preparations of the D23580 invasive African isolate of Salmonella Typhimurium. The absolute number of IFNγ-producing cells in innate, innate-like and adaptive lymphocyte subpopulations was determined. Principal Findings Early IFNγ production was found in the innate/innate-like lymphocyte subsets: γδ-T cells, NK cells and NK-like T cells. Significantly higher percentages of such cells produced IFNγ compared to adaptive αβ-T cells (Student's t test, P<0.001 and ≤0.02 for each innate subset compared, respectively, with CD4+- and CD8+-T cells). The absolute numbers of IFNγ-producing cells showed similar differences. The proportion of IFNγ-producing γδ-T cells, but not other lymphocytes, was significantly higher when stimulated with live compared with heat-killed bacteria (P<0.0001). Conclusion/Significance Our findings indicate an inherent capacity of innate/innate-like lymphocyte subsets to produce IFNγ early in the response to Salmonella infection. This may serve to control intracellular infection and reduce the threat of extracellular spread of disease with bacteremia which becomes life-threatening in the absence of protective antibody. These innate cells may also help mitigate against the effect on IFNγ production of depletion of Salmonella-specific CD4+-T lymphocytes in HIV infection

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients. To investigate whether the lymphocyte accumulation was due to a higher lymphocyte production, an altered homeostasis, or a differential transmigration of lymphocyte subsets through endothelia, T-cell receptor excision circles and kappa-deleting recombination excision circles were quantified before and after treatment, T-cell receptor repertoire was analyzed by spectratyping, and T- and B-lymphocyte subset migration was studied using transwell coated with vascular and lymphatic endothelial cells. We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an enlargement of T-cell heterogeneity. Because new lymphocyte production ensures the integrity of immune surveillance, its quantification could be used to monitor natalizumab therapy safety

Immune reconstitution after allogeneic hematopoietic stem cell transplantation in children: a single institution study of 59 patients

PurposeLymphocyte subset recovery is an important factor that determines the success of hematopoietic stem cell transplantation (HSCT). Temporal differences in the recovery of lymphocyte subsets and the factors influencing this recovery are important variables that affect a patient's post-transplant immune reconstitution, and therefore require investigation.MethodsThe time taken to achieve lymphocyte subset recovery and the factors influencing this recovery were investigated in 59 children who had undergone HSCT at the Department of Pediatrics, The Catholic University of Korea Seoul St. Mary's Hospital, and who had an uneventful follow-up period of at least 1 year. Analyses were carried out at 3 and 12 months post-transplant. An additional study was performed 1 month post-transplant to evaluate natural killer (NK) cell recovery. The impact of pre- and post-transplant variables, including diagnosis of Epstein-Barr virus (EBV) DNAemia posttransplant, on lymphocyte recovery was evaluated.ResultsThe lymphocyte subsets recovered in the following order: NK cells, cytotoxic T cells, B cells, and helper T cells. At 1 month post-transplant, acute graft-versus-host disease was found to contribute significantly to the delay of CD16+/56+ cell recovery. Younger patients showed delayed recovery of both CD3+/CD8+ and CD19+ cells. EBV DNAemia had a deleterious impact on the recovery of both CD3+ and CD3+/CD4+ lymphocytes at 1 year post-transplant.ConclusionIn our pediatric allogeneic HSCT cohort, helper T cells were the last subset to recover. Younger age and EBV DNAemia had a negative impact on the post-transplant recovery of T cells and B cells

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells

Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands

Cytomegalovirus (CMV), similar to other members of the Herpesviridae family, can establish both persistent and latent infections. Each of the CMVs that are found in many animal species replicates in the salivary gland, and oral secretion represents a source of horizontal transmission. Locally restricted replication characterizes the immunocompetent individual, whereas in the immunocompromised host, protean disease manifestations occur due to virus dissemination. The virus is cleared by immune surveillance, and CD8+ T lymphocytes play a major role. Remarkably, certain cell types of salivary gland tissues are exempt from CD8+ T-lymphocyte control of murine CMV infection and require the activity of CD4+ T lymphocytes. The results presented here suggest that this activity is a function of Th1 cells. Neutralization of endogenous gamma interferon abrogated the antiviral activity of Th1 cells but not that of CD8+ T lymphocytes in other tissues. Neutralization of endogenous gamma interferon did not interfere with the induction of the cellular and humoral immune response but acted during the effector phase. Recombinant gamma interferon could not replace the function of Th1 cells in vivo and had limited direct antiviral activity in vitro. The results therefore suggest that gamma interferon represents one, but not the only, essential factor involved in salivary gland clearance, establishment of CMV latency, and, eventually, the control of horizontal transmission

Inflammation in chronic degenerative disorders: A novel CD3+CD56+ subset that regulates CD8+ T cell effector function.

It has been reported that a growing and heterogeneous group of regulatory cell modulate immune response. In particular, regulation of CD8+ T lymphocyte effector functions is critical for tissue homeostasis and immune tolerance control. Here, we report that the co-expression of CD3 and CD56 molecules identify a novel human regulatory T cell population exerting suppressive activity on proliferation, cytotoxicity and IFN- production of TCR-activated human CD8+ T lymphocytes. Regulatory functions of human circulating CD3+CD56+ T lymphocytes require cell-to-cell contact and are exerted in both autologous and allogeneic conditions. Of note, CD3+CD56+ T cells are reduced and functionally impaired in children affected by Type 1 Diabetes (T1D), at disease onset. Conversely the frequency of this cell subset is increased in patients with prostate cancer. Taken together, our findings reveal that freshly isolated human CD3+CD56+ cells specifically control activation of human CD8+ T lymphocytes. Perturbation of number and function of this cell subset may account for the deranged functions of CD8+ T lymphocytes observed in autoimmune conditions, including T1D. Thus, therapeutic manipulation of CD3+CD56+ cells may represent an innovative approach to restore immune function in T1D

JC virus-DNA detection is associated with CD8 fffector accumulation in peripheral blood of patients with multiple sclerosis under natalizumab treatment, independently from JC virus serostatus

Although natalizumab (anti-α4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (N0), 1-12 (N12), 13-24 (N24), 25-36 (N36), and over 36 (N > 36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of the N0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV-) (p < 0.01 and p < 0.001, resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curve p = 0.001). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, for N12 and N24 groups (p < 0.01). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation