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. 2013 Mar 13;5(176):176ra32.
doi: 10.1126/scitranslmed.3005191.

Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination

Salah-Eddine Bentebibel  1 , Santiago Lopez, Gerlinde Obermoser, Nathalie Schmitt, Cynthia Mueller, Carson Harrod, Emilio Flano, Asuncion Mejias, Randy A Albrecht, Derek Blankenship, Hui Xu, Virginia Pascual, Jacques Banchereau, Adolfo Garcia-Sastre, Anna Karolina Palucka, Octavio Ramilo, Hideki Ueno
Affiliations

Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination

Salah-Eddine Bentebibel et al. Sci Transl Med. .

Abstract

Seasonal influenza vaccine protects 60 to 90% of healthy young adults from influenza infection. The immunological events that lead to the induction of protective antibody responses remain poorly understood in humans. We identified the type of CD4+ T cells associated with protective antibody responses after seasonal influenza vaccinations. The administration of trivalent split-virus influenza vaccines induced a temporary increase of CD4+ T cells expressing ICOS, which peaked at day 7, as did plasmablasts. The induction of ICOS was largely restricted to CD4+ T cells coexpressing the chemokine receptors CXCR3 and CXCR5, a subpopulation of circulating memory T follicular helper cells. Up to 60% of these ICOS+CXCR3+CXCR5+CD4+ T cells were specific for influenza antigens and expressed interleukin-2 (IL-2), IL-10, IL-21, and interferon-γ upon antigen stimulation. The increase of ICOS+CXCR3+CXCR5+CD4+ T cells in blood correlated with the increase of preexisting antibody titers, but not with the induction of primary antibody responses. Consistently, purified ICOS+CXCR3+CXCR5+CD4+ T cells efficiently induced memory B cells, but not naïve B cells, to differentiate into plasma cells that produce influenza-specific antibodies ex vivo. Thus, the emergence of blood ICOS+CXCR3+CXCR5+CD4+ T cells correlates with the development of protective antibody responses generated by memory B cells upon seasonal influenza vaccination VSports手机版. .

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Fig. 1
Fig. 1
Seasonal influenza vaccines induce ICOS+CXCR5+ cells in blood. (A) Gating strategy for the analysis of blood CXCR5+CD4+ T cell subsets. (B) Percentage of ICOS+ cells within CD4+ T cells. Fresh blood samples were obtained from a healthy adult cohort (n = 12) before and after vaccination with trivalent seasonal influenza vaccine (Fluzone 2009/2010). The right panel shows data from six adults who received injection of normal saline. One-way analysis of variance (ANOVA). ***P < 0.001, paired t test. (C) A representative result of expression of ICOS on CXCR5+CD4+ T cells on day 7 after influenza vaccination or injection of normal saline. (D) Percentage of ICOS+ cells within CXCR5+ and CXCR5−CD4+ T cell compartments before and after influenza vaccination. Paired t test. n.s., not significant.
Fig. 2
Fig. 2
ICOS is expressed by CXCR3+CXCR5+CD4+ T cells. (A) ICOS expression on CXCR5+ TH subsets before and 7 days after influenza vaccination. A representative result is shown. (B) Percentage of ICOS+ cells in CXCR5+ TH subsets before and 7 days after influenza vaccination in the two cohorts. Paired t test. (C) Expression of PD-1 and Bcl-6 by ICOS+CXCR3+CXCR5+CD4+ T cells (red), ICOS−CXCR3+CXCR5+CD4+ T cells (blue), and CXCR3−CD4+ T cells (gray). A representative of three experiments is shown.
Fig. 3
Fig. 3
Increase of CXCR3+CXCR5+CD4+ T cells after influenza vaccination. (A) Increase of CXCR3+ cells in CXCR5+CD4+ T cell populations. The composition of the indicated subsets within the CXCR5+CD4+ T cells before and 7 days after influenza vaccination in the two cohorts. Paired t test. (B) Correlation between the increase of CXCR3+ cells in CXCR5+CD4+ T cells (y axis) and the increase of ICOS on CXCR3+CXCR5+CD4+ cells.
Fig. 4
Fig. 4
ICOS+CXCR3+CXCR5+CD4+ T cells correlate with antibody responses. (A) Correlation between the increase of global antibody (HI and VN) titers and the increase of ICOS+CXCR3+CXCR5+CD4+ T cells. (B) Correlation between the increase of global HI antibody titers and absolute number of ICOS+CXCR3+CXCR5+CD4+ T cells at day 7 (top) and CD38+CD27+ plasmablasts at day 7 (bottom). (C) Absolute number of plasmablasts in blood before and 7 days after influenza vaccination in the two cohorts. Paired t test. (D) Correlation between the increase in the absolute number of ICOS+CXCR3+CXCR5+CD4+ T cells in blood and the increase in the absolute number of CD38+CD27+ plasmablasts. (E) Correlation between the increase of global antibody (HI and VN) titers and the increase of ICOS+CXCR3+CXCR5+CD4+ T cells in the 2011/2012 adult cohort. n = 37. (F) Correlation between the increase of HI titers against three different hemagglutinin included in the vaccines and the increase of ICOS+ CXCR3+CXCR5+CD4+ T cells in the children cohort. (G) Correlation between the increase of HI titers against H1N1 2009 and the increase of ICOS+CXCR3+CXCR5+CD4+ T cells in children who did not carry preexisting antibodies (bottom) and in children who showed preexisting specific antibodies (HI titer ≥ ×40, top).
Fig. 5
Fig. 5
ICOS+CXCR3+CXCR5+CD4+ T cells are specific for influenza antigens. (A) Ki67 expression by ICOS+CXCR3+CXCR5+CD4+ T cells at day 7 after vaccination (n = 3). A representative result is shown on the top panels. (B) CD154 assay. PBMCs obtained at day 7 after vaccination were stimulated with either Fluzone or heat-killed PR8 influenza virus for 6 hours. CD154+ cells represent antigen-specific cells. Gated to CXCR5+CD4+ and CXCR5−CD4+ T cells. A representative from experiments with four donors. (C) The percentage of CD154+ cells within ICOS+ and ICOS− cells among the CXCR5+ and CXCR5−CD4+ T cells upon stimulation with Fluzone (top) and PR8 virus (bottom). n = 4. ***P < 0.001, one-way ANOVA.
Fig. 6
Fig. 6
ICOS+CXCR3+CXCR5+CD4+ T cells express multiple cytokines including IL-21. (A) Intracytoplasmic cytokine expression by CXCR5+CD4+ T cells stimulated with Fluzone. A representative from experiments with four donors. (B) Cytokine expression by CD154+CXCR5+CD4+ T cells induced by Fluzone stimulation. Expression of the indicated cytokines and ICOS. A representative from experiments with four donors. (C) Frequency of cytokine-expressing cells among CD154+ICOS+CXCR5+ and ICOS−CXCR5+CD4+ T cells induced by Fluzone stimulation. n = 4. Paired t test. **P < 0.01, *P < 0.05. (D) Cytokine expression pattern of CD154+ICOS+CXCR5+ and ICOS−CXCR5+CD4+ T cells induced by Fluzone stimulation. n = 4. The numbers of expressed cytokines are shown on the right in pie charts.
Fig. 7
Fig. 7
ICOS+CXCR3+CXCR5+CD4+ T cells help memory B cells. (A and B) Differentiation of naïve B cells cocultured with CXCR5+ TH subsets. Naïve B cells cultured for 12 days with the indicated CXCR5+ TH subsets (from day 7 after vaccination) were analyzed for the expression of CD38 and CD138. (A) Representative result of four experiments. (B) The number of total B cells, plasmablasts, and plasma cells in the cultures was determined on day 12. n = 4. ***P < 0.001, **P < 0.01, *P < 0.05, one-way ANOVA. (C and D) Memory B cell differentiation. Memory B cells cultured for 6 days with the indicated CXCR5+ TH subsets were analyzed for the expression of CD38 and CD138. (C) Representative result of four experiments. (D) The number of total B cells, plasmablasts, and plasma cells in the cultures was determined on day 6. n = 4. One-way ANOVA. Blocking of IL-10 and IL-21. (E) Blocking reagents were added to the cultures of memory B cells and ICOS+CXCR3+CXCR5+CD4+ T cells. The number of plasma cells induced in the cultured wells was determined. n = 3. One-way ANOVA. (F) T cell recovery and IL-2 production. The indicated CXCR5+ TH subsets were cultured with memory B cells. The number of recovered viable CD4+ T cells at day 6 (left) and IL-2 levels in the supernatants at day 2 (right) are shown. n = 4. One-way ANOVA.
Fig. 8
Fig. 8
ICOS+CXCR3+CXCR5+CD4+ T cells induce antigen-specific antibody response. (A) Proliferation of CD4+ T cells. CXCR5+ TH subsets were cultured with memory B cells loaded with Fluzone. The number of CD4+ T cells in the cultures was determined on day 6. Two independent experiments. (B) Cytokine levels on day 2 of culture supernatants. A representative of two experiments. (C and D) The expression of CD38 and CD138 on B cells was determined on day 6. (C) Representative result of three experiments. (D) The number of total B cells, plasmablasts, and plasma cells in the cultures was determined on day 6. n = 3. One-way ANOVA. (E) Influenza-specific IgG levels on day 6. n = 3.
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References

    1. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N. Engl. J. Med. 1994;331:778–784. - PubMed
    1. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: A systematic review and meta-analysis. Lancet Infect. Dis. 2012;12:36–44. - PubMed
    1. King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu. Rev. Immunol. 2008;26:741–766. - "V体育2025版" PubMed
    1. Crotty S. Follicular helper CD4 T cells (TFH) Annu. Rev. Immunol. 2011;29:621–663. - PubMed
    1. Victora GD, Nussenzweig MC. Germinal centers. Annu. Rev. Immunol. 2012;30:429–457. - "V体育ios版" PubMed

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