scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Cd4 T Cells ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between children and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA. Results: Our results found that childhood mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4 + T-bet + IFN-γ + Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4 + GATA3 + IL-4 + Th2 cells and CD4 + CXCR5 + Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4 + or activated CD4 + T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4 + T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between children and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown.Methods: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA.Results: Our results found that childhood mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group.Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2019 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Cd4 T Cells ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Ifn Γ ◽  
Old Mice

Abstract Background As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between childhood and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods 4 and 8-week-old mice were used to mimic childhood and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-special IgG were measured by ELISA. Results Infant mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4 + T-bet + IFN-γ + Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4 + GATA3 + IL-4 + Th2 cells and CD4 + CXCR5 + Tfh cells, and IL-4 production in the 8-week-old mice obviously increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-special IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4 + or activated CD4 + T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusion We consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4 + T cells exhaustion.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between childhood and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods: 4 and 8-week-old mice were used to mimic childhood and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA. Results: Our results found that childhood mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between children and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA. Results: Our results found that childhood mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Cd4 T Cells ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between childhood and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown.Methods: 4 and 8-week-old mice were used to mimic childhood and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-special IgG were measured by ELISA.Results: Our results found that infant mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4 + T-bet + IFN-γ + Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4 + GATA3 + IL-4 + Th2 cells and CD4 + CXCR5 + Tfh cells, and IL-4 production in the 8-week-old mice obviously increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-special IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4 + or activated CD4 + T cells in the 8-week-old mice as compared to the 4-week-old group.Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4 + T cells exhaustion.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Adaptive Immune Response ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: It is important to expound the opposite clinical outcomes between children and adulthood for eradicate malaria. There remains unknown about the correlation between adaptive immune response and age-related in malaria.. Methods: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA. Results: The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

Abstract 001: Axl Expression by CD4+ T Lymphocytes Promotes Salt-Dependent Hypertension

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Kristine M Wadosky ◽  
Sri N Batchu ◽  
Angie Hughson ◽  
Kathy Donlon ◽  
Craig N Morrell ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
White Blood Cells ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Salt Hypertension ◽  
Ifn Γ

Introduction: Our laboratory has shown that Axl, a receptor tyrosine kinase, is important in both vascular and immune functions during deoxycorticosterone acetate (DOCA)-salt hypertension. We hypothesized that Axl activity specifically in T lymphocytes could explain the dependence of hypertension on Axl. Methods and Results: We did adoptive transfers of either Axl+/+ or Axl-/- CD4+ T cells to RAG1-/- mice that lack mature T cells. Once CD4+ T cell repopulations were confirmed, we induced DOCA-salt hypertension for 6 weeks. Systolic blood pressure (BP, mmHg) increased by 20±5 in Axl+/+RAG-/- mice after DOCA-salt, but Axl-/- RAG-/- mice had increases in BP by only 6+3 after 6 weeks of DOCA-salt. We isolated naïve CD4+ T cells from both Axl+/+ and Axl-/- littermates and primed them under either Th1 or Th2 polarizing conditions in culture. Production of interferon gamma (IFN-γ ng/mL) was significantly decreased (-23%, p<0.05) in Axl-/- (396±23) compared to Axl+/+ (512±42) under Th1-priming. However, Axl had no effect on interleukin 4 (IL-4, ng/mL) production under Th2 polarizing conditions. Intracellular staining of the Th1/Th2 cells with IFN-γ and IL-4 antibodies by flow cytometry confirmed expression of cytokines in culture media. Complete blood counts showed that Axl-/- mice had significantly lower white blood cells due to decreased numbers of lymphocytes (4.5±0.7x10 9 ) compared to Axl+/+ mice (7.8±0.7x10 9 ). We found a higher population of AnnexinV (marker of early apoptosis)-positive peripheral leukocytes in Axl-/- mice (10±1%) compared to Axl+/+ (4±1%) by flow cytometry; while the percentages of dead cells (~10%) were similar between Axl+/+ and Axl-/- mice. Conclusions: Altogether we show that expression of Axl by T cells drives salt-induced hypertension. The mechanism of Axl-dependent effects on T cells occurs via T-cell-dependent expression of the pro-inflammatory cytokine IFN-γ. In addition, Axl plays a role in inhibiting lymphocyte apoptosis in the circulation. Future work will focus on how Axl expression in T cells affects T cell-dependent vascular remodeling during hypertension.

Functional Characterization of CD4+ T-Cells in Aplastic Anemia (AA)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1340-1340 ◽  
Author(s):  
Shahram Y Kordasti ◽  
Judith C. W. Marsh ◽  
Sufyan Al-Khan ◽  
Jie Jiang ◽  
Alexander E Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Treatment Group ◽  
High Throughput ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Absolute Number ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Ifn Γ ◽  
Pre Treatment

Abstract Abstract 1340 We have examined the role of CD4+ T-cells in the pathogenesis of AA in 63 patients, 48 of whom were analyzed at diagnosis and 15 following immunosuppressive therapy (IST). Absolute numbers of CD4+ regulatory T cells (Tregs, defined as CD3+CD4+CD25highCD27+Foxp3+) were lower in pre-treatment AA patients compared to 10 healthy donors (HDs) (5.5 × 106 v 1.4 × 107)(p=0.01). In patients with severe (SAA) and very severe AA (VSAA), the absolute number and frequency of Tregs were lower than non-severe AA (NSAA) (4.4 × 106/L v 1 × 107/L)(p=0.01) and HDs (4.4 × 106/L v 3 × 107/L) (p<0.001). Absolute numbers of Th1 and Th2 cells in all pre-treatment patients were higher compared to HDs (6.4 × 107/L v 1.8 × 107/L)(p=0.03) for Th1 and (2.6 × 107/L v 2.4 × 106/L)(p=0.006) Th2 cells. Although mean percentages of AA Th17 cells were higher than in HDs (1.5% v 0.15%)(p=0.04), differences in absolute numbers were not significant. Absolute numbers of Th2 and Th17 cells were increased in SAA (1.3 × 107/L v 7.4 × 106/L for Th2)(p=0.01) compared to NSAA (5.7 × 106/L v 2.15 × 106/L for Th17)(p=0.02). Ratios of Th1/Tregs (p=0.003), Th2/Tregs (p=0.02), and Th17/Tregs (p=0.001) were higher in SAA and VSAA compared to NSAA. Percentage of both activated (CD4+CD45RA−CD25highFoxp3high) and resting (CD4+CD45RA+ CD25highFoxp3low) Tregs was decreased in AA patients, compared to HDs (p=0.004 and p=0.01), whereas cytokine secreting Tregs (CD4+CD45RA−CD25high Foxp3low) were increased in AA (p<0.003). Sorted Tregs from AA patients did not suppress cytokine secretion by autologous or HD T effectors (Te) cells in 1:1 co-cultures, whereas IL-2 and IFN-γ secretion by AA Te (CD4+CD25lowCD127high) was suppressible by allogeneic Tregs from HDs, confirming Tregs dysfunction. AA Tregs did not inhibit either CD154 or CD69 expression on Te cells. Tregs from AA patients secreted significantly more IFN-γ, TNF-α and IL-17 (p=0.02, p=0.02 and p=0.01, respectively) after 4 hours stimulation with PMA/Ionomycine compared to HDs. Expression levels of FoxP3, ROR□c and T-bet in AA Tregs was normal. IFN-γ secreting cells (Th1) were enriched using enrichment kit then further enriched by FACS sorting. CDR3 region products of TCR Vβ-chain were amplified using Vβ specific forward and Cβ reverse primers. CDR3 PCR products from AA patients and HDs were subjected 454 sequencing (Roche GS FLX titanium). Sequencing was performed to yield an average ‘depth’ in excess of 1000 clonally reads (1000x) for each sample specific CDR3 PCR amp icon. Reads were processed using Roche Amp icon Variant Analyzer software (AVA). Diversity of TCR receptors (measured by spectratyping and confirmed by high throughput deep sequencing) in AA Th1 cells was lower than HDs (p=0.037), as shown by the percentage and number of consensus clusters in total sequence reads. Interestingly, percentages of the most dominant CDR3 clones, revealed by high throughput sequencing, were higher in AA compared to HDs, regardless of spectratyping pattern. Global gene expression of Tregs was compared in 3 pre-IST AA patients and 5 HDs. A unique gene signature consisting of 86 genes that were significant was identified. There were 8 down regulated genes (fold change) in the pre-treatment group; PIN4 (−4.1), OR2T12 (−3.3), AMAC1 (−2.73), PERP (−2.69), UTS2 (−2.27), RNF139 (−2.13), COMMD9 (−2.09) and LOC100128356 (−2.01). The top 10 of 78 up-regulated genes in the pre-treatment group were HBB (19.5), PSME2 (13.8), CSDA (13.07), FAM127A (7.78), EXOSC1 (7.73), BPGM (7.43), CYSLTR1 (7.17), CHPT1 (6.96) and PLAC8 (6.71). qPCR analysis for CSDA, HBB, PSMiE2, PERP, PIN4, and UTS2 confirmed a similar trend to the microarray results. Interestingly absolute number of Tregs, and Th2/Treg ratio were higher in 10 IST responsive patients compared to 5 non-responsive patients (p=0.005 and 0.02, respectively). We show that expansion of Th1, Th2, Th17, and decreased/skewed Tregs immunophenotype and function are a consistent and defining feature of SAA and VSAA. Clonal expansion of Th1 cells is likely to be antigen driven and the presence of dysfunctional Tregs aggravates this autoimmune response. Increases of Tregs, and Th2/Treg ratios following IST predicts a favourable response to this treatment. Disclosures: No relevant conflicts of interest to declare.

Reciprocal Interactions Between Conventional CD4 T Cells and Regulatory T Cells Alter the Properties of Regulatory T Cells and Promote the Development of IL-17 Producing Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 709-709
Author(s):  
Lequn Li ◽  
Jin Sub Kim ◽  
Vassiliki A Boussiotis
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Treg Cells ◽  
Culture Conditions ◽  
Th2 Cells ◽  
Reciprocal Interactions ◽  
Ifn Γ ◽  
Th1 And Th2

Abstract Abstract 709 The differentiation and functional specialization of effector T cells allows for effective immune response to diverse insults. However, tight regulation of effector T cell responses is required for effective control of infections and avoidance of autoimmunity. Naïve CD4 T cells can differentiate into IFN-γ-secreting type I (Th1) cells and IL-4-secreting type II (Th2) cells. Recently, the Th1/Th2 paradigm of T helper (Th) cells differentiation has been expanded following the discovery of a third subset of effector Th cells that produce IL-17 (Th17). Regulatory T (Treg) cells have a remarkable ability to prevent naïve T cell differentiation into Th1 and Th2 cells and to suppress immune responses driven by Th1 and Th2 effector cells. The role of Treg cells in regulating IL-17 production remains undetermined. Some studies suggest that Treg cells may promote differentiation of naïve T cells into Th17 cells in the context of inflammatory cytokine milieu. The aim of our present study was to determine the role of Treg cells and conventional CD4+ T cells (Tconv) in the differentiation of IL-17 producing cells in the absence of exogenous cytokines and insults. Naïve Tconv cells stimulated with anti-CD3 mAb in the presence of antigen presenting cells (APCs) secreted significant amounts of IFN-γ and IL-4 but no detectable levels of IL-17, whereas Treg cells were incapable of producing any of these cytokines under the same culture conditions. Production of IFN-γ and IL-4 was significantly reduced by addition of Treg cells in the cultures of Tconv cells with anti-CD3 mAb and APC. In contrast, production of IL-17 was considerably enhanced in these co-culture conditions and the level of IL-17 displayed a positive correlation with the number of Treg cells added in the culture. To evaluate whether TCR-mediated stimulation of both Treg and Tconv cells was required for IL-17 production, we used Tconv cells and Treg cells from two different TCR transgenic mouse strains in H-2b background, 2D2 (MOG35-55-specific) and OT-II (OVA323-339-specific), respectively, and co-cultured them in the presence of APCs (H-2b). Production of IL-17 was not observed when either MOG peptide or OVA peptide alone was added in the cultures. In contrast, addition of both MOG and OVA resulted in production of IL-17, suggesting that simultaneous activation of Tconv and Treg cells was essential for induction of IL-17. To determine the source of IL-17 during co-culture of Treg and Tconv cells, we purified Treg cells from C57/B6 mice and co-cultured them with Tconv cells from the B6 congenic mouse strain B6.PL, which carry the Thy1a (Thy1.1) allele and can be easily recognized by flow cytomeric analysis using a Thy1.1-specific mAb. Detailed evaluation during co-culture revealed that a significant proportion of Thy1.1- T cells (the source of Treg) gradually downregulated expression of Foxp3 while obtaining expression of IL-17. In contrast, there was no significant change in the expression of either Foxp3 or IL-17 in the Thy1.1+ population (the source of Tconv), suggesting that Treg was the main source of IL-17 when stimulated in the presence of antigen and activated Tconv cells. Several cytokines have been implicated in the induction of IL-17, in particular, TGF-β. For this reason, we investigated the potential involvement of TGF-β in this conversion process. Addition of TGF-β to Tconv cultured with APCs and anti-CD3 mAb in the absence of Treg cells resulted in upregulation of Foxp3 but not IL-17. In contrast, addition of TGF-β neutralizing antibody to Tconv cultured with APC and anti-CD3 mAb in the presence of Treg, suppressed IL-17 production. Moreover, assessment of TGF-β signaling in Tconv and Treg cells revealed a dramatically increased level of Smad3 phosphorylation in Treg compared to Tconv cells, indicating a reduced threshold of TGF-β mediated signaling in Treg cells. Taken together, our data indicate that reciprocal interactions of Treg and Tconv cells are required for conversion of Treg into IL-17 producing cells and that TGF-β-mediated signaling is required for this process. In addition, our results provide evidence that Treg may convert into proinflammatory effectors producing IL-17, under conditions that promote Tconv differentiation into Treg cells. These observations provide a new dimension to our understanding of Treg cells functions and may have important implications in therapeutic strategies using Treg cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

2001 ◽  
Vol 194 (2) ◽  
pp. 143-154 ◽  
Author(s):  
Ronald B. Smeltz ◽  
June Chen ◽  
Jane Hu-Li ◽  
Ethan M. Shevach
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Th2 Cells ◽  
T Helper ◽  
Activated T Cells ◽  
T Cell Stimulation ◽  
Ifn Γ ◽  
Α Chain ◽  
Th 1

Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12–mediated interferon (IFN)-γ production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor α chain (IL-18Rα) expression. The majority of peripheral CD4+ T cells constitutively expressed the IL-18Rα. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18Rα expression was observed. IL-12–mediated upregulation of IL-18Rα required IFN-γ. Activated CD4+ T cells that expressed low levels of IL-18Rα could produce IFN-γ when stimulated with the combination of IL-12 and IL-18, while CD4+ cells which expressed high levels of IL-18Rα could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Rα expression. Both IL-4−/− and signal transducer and activator of transcription (Stat)6−/− T cells expressed higher levels of IL-18Rα after TCR stimulation. Furthermore, activated T cells from Stat6−/− mice produced more IFN-γ in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18Rα by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.

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