Dataset Information

Donor CD8 T cells and IFN-gamma are critical for sex-based differences in donor CD4 T cell engraftment and lupus-like phenotype in short-term chronic graft-versus-host disease mice.

ABSTRACT: The transfer of unfractionated DBA/2J (DBA) splenocytes into B6D2F(1) (DBA ? F(1)) mice results in greater donor CD4 T cell engraftment in females at day 14 that persists long-term and mediates greater female lupus-like renal disease. Although donor CD8 T cells have no demonstrated role in lupus pathogenesis in this model, we recently observed that depletion of donor CD8 T cells prior to transfer eliminates sex-based differences in renal disease long-term. In this study, we demonstrate that greater day 14 female donor CD4 engraftment is also critically dependent on donor CD8 T cells. Male DBA ? F(1) mice exhibit stronger CD8-dependent day 8-10 graft-versus-host (GVH) and counter-regulatory host-versus-graft (HVG) responses, followed by stronger homeostatic contraction (days 10-12). The weaker day 10-12 GVH and HVG in females are followed by persistent donor T cell activation and increasing proliferation, expansion, and cytokine production from days 12 to 14. Lastly, greater female day 14 donor T cell engraftment, activation, and cytokine production were lost with in vivo IFN-? neutralization from days 6 to 14. We conclude the following: 1) donor CD8 T cells enhance day 10 proliferation of donor CD4 T cells in both sexes; and 2) a weaker GVH/HVG in females allows prolonged survival of donor CD4 and CD8 T cells, allowing persistent activation. These results support the novel conclusion that sex-based differences in suboptimal donor CD8 CTL activation are critical for shaping sex-based differences in donor CD4 T cell engraftment at 2 wk and lupus-like disease long-term.

SUBMITTER: Foster AD

PROVIDER: S-EPMC3215299 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Donor CD8 T cells and IFN-gamma are critical for sex-based differences in donor CD4 T cell engraftment and lupus-like phenotype in short-term chronic graft-versus-host disease mice.

Foster Anthony D AD Soloviova Kateryna K Puliaeva Irina I Puliaiev Maksym M Puliaev Roman R Finkelman Fred F Via Charles S CS

Journal of immunology (Baltimore, Md. : 1950) 20110429 11

The transfer of unfractionated DBA/2J (DBA) splenocytes into B6D2F(1) (DBA → F(1)) mice results in greater donor CD4 T cell engraftment in females at day 14 that persists long-term and mediates greater female lupus-like renal disease. Although donor CD8 T cells have no demonstrated role in lupus pathogenesis in this model, we recently observed that depletion of donor CD8 T cells prior to transfer eliminates sex-based differences in renal disease long-term. In this study, we demonstrate that grea ...[more]

PMID: 21531893

Similar Datasets

Project description:Protein subunit vaccines present a compelling new area of research for control of tuberculosis (TB). Based on the interaction between Mycobacterium tuberculosis and its host, five stage-specific antigens of M. tuberculosis that participate in TB pathogenesis--Rv1813, Rv2660c, Ag85B, Rv2623, and HspX--were selected. These antigens were verified to be recognized by T cells from a total of 42 whole blood samples obtained from active TB patients, patients with latent TB infections (LTBIs), and healthy control donors. The multistage polyprotein A1D4 was developed using the selected five antigens as a potentially more effective novel subunit vaccine. The immunogenicity and protective efficacy of A1D4 emulsified in the adjuvant MTO [monophosphoryl lipid A (MPL), trehalose-6,6'-dibehenate (TDB), components of MF59] was compared with Bacillus Calmette-Guerin (BCG) in C57BL/6 mice. Our results demonstrated that A1D4/MTO could provide more significant protection against M. tuberculosis infection than the PBS control or MTO adjuvant alone judging from the A1D4-specific Th1-type immune response; however, its efficacy was inferior to BCG as demonstrated by the bacterial load in the lung and spleen, and by the pathological changes in the lung. Antigen-specific single IL-2-secreting cells and different combinations with IL-2-secreting CD4+ T cells were beneficial and correlated with BCG vaccine-induced protection against TB. Antigen-specific IFN-γ+ IL-2+ CD4+ T cells were the only effective biomarker significantly induced by A1D4/MTO. Among all groups, A1D4/MTO immunization also conferred the highest number of antigen-specific single IFN-γ+ and IFN-γ+ TNF-α+ CD4+ T cells, which might be related to the antigen load in vivo, and single IFN-γ+ CD8+ T cells by mimicking the immune patterns of LTBIs or curable TB patients. Our strategy seems promising for the development of a TB vaccine based on multistage antigens, and subunit antigen A1D4 suspended in MTO adjuvant warrants preclinical evaluation in animal models of latent infection and may boost BCG vaccination.

Project description:Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-? secreting cells. However, T-cells are capable of producing many more functions than just IFN-?, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-? secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive individuals for the extent to which gated CD4+ and CD8+ IFN-? producing and non-producing T-cells also secreted IL-2, Perforin, and TNF-? functions. Similarly, the extent of missed virus-specific responses in IFN-? ELISpot assay negative T-cells from 5 HIV-1 uninfected individuals was evaluated. Cells from HIV-infected individuals were stimulated with pooled consensus group M (Con M) peptides; and those from healthy individuals were stimulated with pooled adenovirus (Ad) peptides. Overall, frequencies of virus-specific IFN-? secreting CD4+ and CD8+ cells were low. Proportions of IFN-? negative CD4+ expressing IL-2, Perforin, or TNF-? to Con M were significantly higher (5 of 7 functional profiles) than the corresponding IFN-? positive CD4+ (0 of 7) T-cell phenotype, p?=?0.02; Fisher's Exact test. Likewise, proportions of CD8+ T-cells expressing other functions were significantly higher in 4 of the 7 IFN-? negative CD8+ T-cells. Notably, newly stimulated Perforin, identified as Perforin co-expression with IL-2 or TNF-?, was significantly higher in IFN-? negative CD8+ T-cell than in the positive CD8+ T-cells. Using SEB, lower responses in IFN-? positive cells were most associated with CD4+ than CD8+ T-cells. These findings suggest that studies evaluating immunogenicity in response to HIV and Adenovirus viral antigens should not only evaluate T-cell responsiveness among IFN-? producing cells but also among those T-cells that do not express IFN-?.

Project description:Visceral leishmaniasis (VL) is a chronic and often fatal disease caused by protozoans of the genus Leishmania that affects millions of people worldwide. Patients with symptomatic VL have an impaired anti-Leishmania-specific CD4+ T-cell response, which is reversed after clinical cure. In contrast, the quality of the CD4+ and CD8+ T-cell responses involved in resistance and/or cure of VL relies on the capability of these cells to activate polyfunctional and memory responses, which are associated with the simultaneous production of three cytokines: IFN-γ, IL-2, and TNF-α. Models for the development of CD4 and CD8 T-cell quality in memory and protection to leishmaniasis have been described previously. We aimed to assess the functionality of the T cells involved in the recovery of the immune suppression throughout the VL treatment. Therefore, we cultured peripheral blood mononuclear cells (PBMCs) from VL patients and healthy controls in vitro with soluble Leishmania antigen (SLA). Cell surface markers and intracellular cytokine production were determined on days 7, 14, 21, 30, 60, 90, and 180 after the beginning of chemotherapy. We observed that the frequencies of CD4+TNF-α+IFN-γ+ and the multifunctional CD4+IL-2+TNF-α+IFN-γ+, together with CD4+TNF-α+ and CD4+IFN-γ+ T cells, increased throughout and at the end of the treatment, respectively. In addition, enhanced frequencies of CD8+IL-2+TNF-α+IFN-γ+ and CD8+TNF-α+IFN-γ T cells were also relevant in the healing process. Noteworthy, the frequencies of the CD4+ and CD8 central-memory T cells, which produce IL-2, TNF-α, and IFN-γ and ensure the memory response against parasite reinfection, are significantly enhanced in cured patients. In addition, the subset of the non-functional CD8Low population is predominant in VL untreated patients and decreases along the chemotherapy treatment. In contrast, a CD8High subset increased towards the cure. Furthermore, the cure due to treatment with meglumine antimoniate or with liposomal amphotericin B was associated with the recovery of the T-cell immune responses. We described the evolution and participation of functional T cells during the treatment of patients with VL. Our results disclosed that the clinical improvement of patients is significantly associated with the participation of the CD4+ and CD8+ cytokine-secreting T cells.

Project description:In Plasmodium falciparum holoendemic transmission regions of western Kenya, life-threatening pediatric malaria manifests primarily as severe malarial anemia (SMA, Hb≤6.0 g/dL with any density parasitemia). To determine the role that CD4+ T-cell-driven inflammatory responses have in the pathogenesis of SMA, peripheral CD4+ T-cell populations and their intracellular production of pro-inflammatory cytokines (IFN-γ and IL-17) were characterized in children aged 12-36 months of age stratified into two groups: non-severe malarial anemia (non-SMA, Hb≥6.0 g/dL, n = 50) and SMA (n = 39). In addition, circulating IFN-γ and IL-17 were measured as part of a Cytokine 25-plex Antibody Bead Kit, Human (BioSource™ International). Children with SMA had higher overall proportions of circulating lymphocytes (P = 0.003) and elevated proportions of lymphocytes expressing IFN-γ (P = 0.014) and comparable IL-17 (P = 0.101). In addition, SMA was characterized by decreased memory-like T-cells (CD4+CD45RA-) expressing IL-17 (P = 0.009) and lower mean fluorescence intensity in memory-like CD4+ T-cells for both IFN-γ (P = 0.063) and IL-17 (P = 0.006). Circulating concentrations of IFN-γ were higher in children with SMA (P = 0.009), while IL-17 levels were comparable between the groups (P = 0.164). Furthermore, circulating levels of IFN-γ were negatively correlated with IL-17 levels in both groups of children (SMA: r = -0.610, P = 0.007; and non-SMA: r = -0.516, P = 0.001), while production of both cytokines by lymphocytes were positively correlated (SMA: r = 0.349, P = 0.037; and non-SMA: r = 0.475, P = 0.001). In addition, this correlation was only maintained by the memory-like CD4+ T cells (r = 0.365, P = 0.002) but not the naïve-like CD4+ T cells. However, circulating levels of IFN-γ were only associated with naïve-like CD4+ T cells producing IFN-γ (r = 0.547, P = 0.028), while circulating levels of IL-17 were not associated with any of the cell populations. Taken together, these results suggest that enhanced severity of malarial anemia is associated with higher overall levels of circulating lymphocytes, enhanced intracellular production of IFN-γ by peripheral lymphocytes and high circulating IFN-γ levels. In addition, the observed inverse relationship between the circulating levels of IFN-γ and IL-17 together with the reduction in the levels of memory-like CD4+ T cells expressing IL-17 in children with SMA may suggest possible relocation of these cells in the deeper tissues for their pathological effect.

Dataset Information

Donor CD8 T cells and IFN-gamma are critical for sex-based differences in donor CD4 T cell engraftment and lupus-like phenotype in short-term chronic graft-versus-host disease mice.

Publications

Donor CD8 T cells and IFN-gamma are critical for sex-based differences in donor CD4 T cell engraftment and lupus-like phenotype in short-term chronic graft-versus-host disease mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets