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T-cell STAT3 is required for the maintenance of humoral immunity to LCMV.

McIlwain DR, Grusdat M, Pozdeev VI, Xu HC, Shinde P, Reardon C, Hao Z, Beyer M, Bergthaler A, Häussinger D, Nolan GP, Lang KS, Lang PA - Eur. J. Immunol. (2014)

Bottom Line: STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types.As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG-secreting cells, resulting in failure to maintain levels of virus-specific IgG or mount neutralizing responses to LCMV in the serum.These effects were associated with reduced control of viral replication and prolonged infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.

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T-Cell STAT3 is required for the maintenance of germinal center B-cell reactions toward LCMV. (A–D) Lck-Cre−Stat3fl/fl vs. Lck-Cre+Stat3fl/fl mice were infected with 2 × 103 PFU LCMV-Docile. (A) Total quantity of (B220+) B cells in the spleen on days 12, 20, 40, and 65 postinfection was measured by flow cytometry (mean ± SEM; n = 4–7 mice/group). (B–D) GC B cells (B220+PNA+FAS+) were measured on days 12, 20, 40, and 65 postinfection (n = 4–7 mice/group). (B) Quantity of B220+PNA+FAS+ cells as a percent of total B cells (B220+) at each time point (mean ± SEM), (C) representative dot plot from day 65 (gated on B220+ cells), and (D) numerical quantification of B220+PNA+FAS+ cells in each group at day 65 (mean ± SEM). Data are pooled from —one or two independent experiments per time point. Statistical significance between groups was determined by Student's t-test.
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fig02: T-Cell STAT3 is required for the maintenance of germinal center B-cell reactions toward LCMV. (A–D) Lck-Cre−Stat3fl/fl vs. Lck-Cre+Stat3fl/fl mice were infected with 2 × 103 PFU LCMV-Docile. (A) Total quantity of (B220+) B cells in the spleen on days 12, 20, 40, and 65 postinfection was measured by flow cytometry (mean ± SEM; n = 4–7 mice/group). (B–D) GC B cells (B220+PNA+FAS+) were measured on days 12, 20, 40, and 65 postinfection (n = 4–7 mice/group). (B) Quantity of B220+PNA+FAS+ cells as a percent of total B cells (B220+) at each time point (mean ± SEM), (C) representative dot plot from day 65 (gated on B220+ cells), and (D) numerical quantification of B220+PNA+FAS+ cells in each group at day 65 (mean ± SEM). Data are pooled from —one or two independent experiments per time point. Statistical significance between groups was determined by Student's t-test.

Mentions: Since Tfh cells support germinal center reactions [13, 24, 25], we next examined the status of B-cell immunity to chronic LCMV in the presence or absence of STAT3. Total B-cell numbers in the spleen were similar across both types of animals (Fig.2A), as were proliferative responses of B cells to LPS or CD40-L (Supporting Information Fig. 3A, B), indicating that T cell specific deletion of STAT3 did not result in gross B-cell defects. Germinal center reactions were strongly induced in both genotypes, with similar levels of germinal center B cells present at day 12 following infection (Fig.2B). However, compared to controls, the quantity of germinal center B cells detectable in STAT3 deficient animals was markedly lower on days 20, 40, and 65 postinfection, indicating that normal germinal center reactions are not sustained in the absence of T cell STAT3 (Fig.2B–D).


T-cell STAT3 is required for the maintenance of humoral immunity to LCMV.

McIlwain DR, Grusdat M, Pozdeev VI, Xu HC, Shinde P, Reardon C, Hao Z, Beyer M, Bergthaler A, Häussinger D, Nolan GP, Lang KS, Lang PA - Eur. J. Immunol. (2014)

T-Cell STAT3 is required for the maintenance of germinal center B-cell reactions toward LCMV. (A–D) Lck-Cre−Stat3fl/fl vs. Lck-Cre+Stat3fl/fl mice were infected with 2 × 103 PFU LCMV-Docile. (A) Total quantity of (B220+) B cells in the spleen on days 12, 20, 40, and 65 postinfection was measured by flow cytometry (mean ± SEM; n = 4–7 mice/group). (B–D) GC B cells (B220+PNA+FAS+) were measured on days 12, 20, 40, and 65 postinfection (n = 4–7 mice/group). (B) Quantity of B220+PNA+FAS+ cells as a percent of total B cells (B220+) at each time point (mean ± SEM), (C) representative dot plot from day 65 (gated on B220+ cells), and (D) numerical quantification of B220+PNA+FAS+ cells in each group at day 65 (mean ± SEM). Data are pooled from —one or two independent experiments per time point. Statistical significance between groups was determined by Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383653&req=5

fig02: T-Cell STAT3 is required for the maintenance of germinal center B-cell reactions toward LCMV. (A–D) Lck-Cre−Stat3fl/fl vs. Lck-Cre+Stat3fl/fl mice were infected with 2 × 103 PFU LCMV-Docile. (A) Total quantity of (B220+) B cells in the spleen on days 12, 20, 40, and 65 postinfection was measured by flow cytometry (mean ± SEM; n = 4–7 mice/group). (B–D) GC B cells (B220+PNA+FAS+) were measured on days 12, 20, 40, and 65 postinfection (n = 4–7 mice/group). (B) Quantity of B220+PNA+FAS+ cells as a percent of total B cells (B220+) at each time point (mean ± SEM), (C) representative dot plot from day 65 (gated on B220+ cells), and (D) numerical quantification of B220+PNA+FAS+ cells in each group at day 65 (mean ± SEM). Data are pooled from —one or two independent experiments per time point. Statistical significance between groups was determined by Student's t-test.
Mentions: Since Tfh cells support germinal center reactions [13, 24, 25], we next examined the status of B-cell immunity to chronic LCMV in the presence or absence of STAT3. Total B-cell numbers in the spleen were similar across both types of animals (Fig.2A), as were proliferative responses of B cells to LPS or CD40-L (Supporting Information Fig. 3A, B), indicating that T cell specific deletion of STAT3 did not result in gross B-cell defects. Germinal center reactions were strongly induced in both genotypes, with similar levels of germinal center B cells present at day 12 following infection (Fig.2B). However, compared to controls, the quantity of germinal center B cells detectable in STAT3 deficient animals was markedly lower on days 20, 40, and 65 postinfection, indicating that normal germinal center reactions are not sustained in the absence of T cell STAT3 (Fig.2B–D).

Bottom Line: STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types.As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG-secreting cells, resulting in failure to maintain levels of virus-specific IgG or mount neutralizing responses to LCMV in the serum.These effects were associated with reduced control of viral replication and prolonged infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.

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Related in: MedlinePlus