Contraction Of CD4 Research Articles

Circulating T Follicular Helper Cell Abnormalities Associated to Different Clinical Forms of Chronic Chagas Disease.

Multiple perturbations of the immune response affecting a range of cells have been reported in Trypanosoma cruzi-infected individuals and associated to clinical manifestations of chronic Chagas disease. There is a paucity of knowledge about the role of T follicular helper (Tfh) cells in this infection. Here, we sought to characterize circulating Tfh (cTfh) cells in chronic Chagas disease patients and to identify potential associations with disease severity in humans. cTfh cells were characterized by flow cytometry in freshly isolated PBMCs from 7 T. cruzi-infected asymptomatic patients (ASYMP), 5 patients with chronic chagasic dilated cardiomyopathy (CCC) and 8 healthy controls, using antibodies against chemokine receptors CXCR5, CXCR3, CCR6, and CCR7. Our results showed significant expansion of CD4+CD45RO+CXCR5+CCR6+ cells in ASYMP and CCC patients, along with a contraction of CD4+CD45RO+CXCR5+CXCR3-CCR6- (cTfh2) cells. ASYMP patients further exhibited decreased CD4+CD45RO+CXCR5+CXCR3+CCR6- (cTfh1) cells and expanded CD4+CD45RO+CXCR5+CXCR3-CCR6+ (cTfh17) cells while CCC patients exhibited significantly increased frequencies of CD4+CD45RO+CXCR5+CCR7+ cells. Linear regression analysis revealed a positive trend of CD4+CD45RO+CXCR5+CXCR3+CCR6+ (cTfh1/17) cells and negative trends of cTfh1 and cTfh2 cells as disease was more severe. There was no correlation between the frequencies of cTfh cells and circulating CD19+IgD-IgG+ cells or serum levels of T. cruzi-specific IgG. These results demonstrate that the cTfh compartment of humans chronically infected with T. cruzi comprises expanded CCR6-expressing cells and reduced cTfh2 cells. The association of discrete phenotypic changes in cTfh subsets with different clinical forms suggests the potential contribution of T follicular helper cells to Chagas heart disease progression.

Bivalent anti-CD3 Fab dimers drive T cells into a highly efficient fratricide with potential clinical application

Abstract Non-covalent anti-CD3 Fab dimers (Bi-Fabs) bind to the TCR/CD3 complex and activate T cells. In the presence of proper co-stimulation, anti-CD3 Bi-Fabs promote T cell cycling and acquisition of effector functions on CD4 and CD8 T cells more robustly than other bivalent antibody species like F(ab′)2 and mAb with the same specificity. Surprisingly, the net effect of anti-CD3 Bi-Fab treatment on T cells in vitro is contraction of CD4 and CD8 T cells, via AICD. This is in contrast with the net T cell proliferation observed with soluble anti-CD3 mAbs that are stimulatory in the presence of proper co-stimulation. Bi-Fab binding to the TCR/CD3 complex, and direct cellular contact with Bi-Fab engaged T cells, are required to observe the net contraction of treated T cells. Using perforin-deficient T cells, and Fas-FasL blockade, we show this net contraction results from T cell apoptosis via Fas-FasL and CTL degranulation. Structural studies on Bi-Fabs suggest a rigid rod like structure. We hypothesize that the rigid rod allows for a potent crosslinking structure with both paratopes from the anti-CD3 Fabs capable to engage effector T cells on fratricide. In vivo, mice injected with anti-CD3 Bi-Fabs present depletion of T cells from blood, and absence of any adverse effects derived from T cell activation like cytokine storm. We have begun exploring the therapeutic potential of T cell depletion in mouse models of autoimmune disease with promising results.

Expandation of CD56-Bright NK Cell in Patients with Steroid-Refractory Graft-Versus-Host Disease Treated with Basiliximab and Etanercept

Objectives: Steroid-resistant aGVHD(SR-aGVHD) is a complication with high incidence of mortality following allogeneic stem cell transplantation. Our previous study has showed combined treatment by basiliximab and etanercept achieved high response in SR-aGVHD. The aim of this study is to investigate the changes of lymphocyte subsets in SR-aGVHD following treatment with basiliximab and etanercept.Methods: We treated 11 SR-aGVHD patients with basiliximab 20mg on days 1, 4, 8, 15, and etanercept 25 mg twice a week for 4 weeks, followed by once weekly for 4 more weeks. Their peripheral blood lymphocyte subsets were assessed by flow cytometry before and after treatment.Results: The overall response to treatment was 100% (11/11) with 72.7% (8/11) achieving a complete response. As expected, we found a significant depletion of both CD4+ and CD8+ T-cell subset at 4w following treatment. Conversely, the proportion of CD3-CD56+NK expanded significantly, accounting for 26.82±7.69% of PB lymphocytes at 6w following treatment, compared with 10.90±3.94% before treating. The increasement in NK proportion lasting from several weeks to several months. Moreover, the percentage of CD56bright and IFN-gamma-producing NK cell subsets also increased after combined treatments.Conclusion: Expansion of CD56(bright) and IFN-gamma production NK cell subsets and contraction of CD4(+) and CD8(+) T cell numbers may contribute to the well control of SRaGVHD by basiliximab and etanercept. This finding provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during aGVHD. DisclosuresNo relevant conflicts of interest to declare.

A Crucial Role for Kupffer Cell-Derived Galectin-9 in Regulation of T Cell Immunity in Hepatitis C Infection

Approximately 200 million people throughout the world are infected with hepatitis C virus (HCV). One of the most striking features of HCV infection is its high propensity to establish persistence (∼70–80%) and progressive liver injury. Galectins are evolutionarily conserved glycan-binding proteins with diverse roles in innate and adaptive immune responses. Here, we demonstrate that galectin-9, the natural ligand for the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), circulates at very high levels in the serum and its hepatic expression (particularly on Kupffer cells) is significantly increased in patients with chronic HCV as compared to normal controls. Galectin-9 production from monocytes and macrophages is induced by IFN-γ, which has been shown to be elevated in chronic HCV infection. In turn, galectin-9 induces pro-inflammatory cytokines in liver-derived and peripheral mononuclear cells; galectin-9 also induces anti-inflammatory cytokines from peripheral but not hepatic mononuclear cells. Galectin-9 results in expansion of CD4+CD25+FoxP3+CD127low regulatory T cells, contraction of CD4+ effector T cells, and apoptosis of HCV-specific CTLs. In conclusion, galectin-9 production by Kupffer cells links the innate and adaptive immune response, providing a potential novel immunotherapeutic target in this common viral infection.

Duration of Infection and Antigen Display Have Minimal Influence on the Kinetics of the CD4+ T Cell Response to Listeria monocytogenes Infection

The T cell response to infection consists of clonal expansion of effector cells, followed by contraction to memory levels. It was previously thought that the duration of infection determines the magnitude and kinetics of the T cell response. However, recent analysis revealed that transition between the expansion and contraction phases of the Ag-specific CD8+ T cell response is not affected by experimental manipulation in the duration of infection or Ag display. We studied whether the duration of infection and Ag display influenced the kinetics of the Ag-specific CD4+ T cell response to Listeria monocytogenes (LM) infection. We found that truncating infection and Ag display with antibiotic treatment as early as 24 h postinfection had minimal impact on the expansion or contraction of CD4+ T cells; however, the magnitudes of the Ag-specific CD4+ and CD8+ T cell responses were differentially affected by the timing of antibiotic treatment. Treatment of LM-infected mice with antibiotics at 24 h postinfection did not prevent generation of detectable CD4+ and CD8+ memory T cells at 28 days after infection, vigorous secondary expansion of these memory T cells, or protection against a subsequent LM challenge. These results demonstrate that events within the first few days of infection stimulate CD4+ and CD8+ T cell responses that are capable of carrying out the full program of expansion and contraction to functional memory, independently of prolonged infection or Ag display.