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OX40 controls effector CD4+ T-cell expansion, not follicular T helper cell generation in acute Listeria infection.

Marriott CL, Mackley EC, Ferreira C, Veldhoen M, Yagita H, Withers DR - Eur. J. Immunol. (2014)

Bottom Line: Mice deficient in OX40 and CD30 showed normal generation of TFH cells but impaired numbers of 2W1S-specific effector cells.OX40 was not expressed by 2W1S-specific memory cells, although it was rapidly up-regulated upon challenge whereupon Ab-ligation of OX40 specifically affected the effector subset.In summary, these data indicate that for CD4(+) T cells, OX40 signals are important for generation of effector T cells rather than TFH cells in this response to acute bacterial infection.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

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Ligation of OX40 upon challenge enhances memory cell expansion and skews phenotype towards T effector memory. Secondary lymphoid tissues were analysed from mice receiving agonistic anti-OX40 or control IgG Abs after challenge. (A) Enumeration of CD44hi2W1S:I-Ab+CD4+ T cells given Abs on the day of challenge. Percentage of CD44hi2W1S:I-Ab+CD4+ T cells that are (B) CXCR5+PD-1+ TFH cells or (C) CXCR5−PD-1− effector cells. (D) Expression pattern of CXCR5 and PD-1 by CD44hi2W1S:I-Ab+CD4+ T cells. (E) Total number of CD44hi2W1S:I-Ab+CD4+ CXCR5+ PD-1+ TFH cells. (F) Enumeration of CD44hi2W1S:I-Ab+ CD4+ T cells from mice given Abs the day after challenge. (G) Immunofluorescence staining of spleen sections DAPI (grey) and expression of Bcl-6 (green), CD3 (blue) and CD4 (red) shown. Magnification 25×, scale bar represents 100 μm. Confocal images are representative of five mice. (H) Area of Bcl-6+ germinal centre (GC) per 1000 μm2 spleen. (I) Absolute number of GCs per 100 000 μm2 spleen. (A–C, E, H, I) Data are pooled from two independent experiments, each data point represents one mouse. Bars show medians. (D) Plots are representative of ≥6 mice pooled from two independent experiments. Mann–Whitney test, *p < 0.05, NS = non-significant.
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fig02: Ligation of OX40 upon challenge enhances memory cell expansion and skews phenotype towards T effector memory. Secondary lymphoid tissues were analysed from mice receiving agonistic anti-OX40 or control IgG Abs after challenge. (A) Enumeration of CD44hi2W1S:I-Ab+CD4+ T cells given Abs on the day of challenge. Percentage of CD44hi2W1S:I-Ab+CD4+ T cells that are (B) CXCR5+PD-1+ TFH cells or (C) CXCR5−PD-1− effector cells. (D) Expression pattern of CXCR5 and PD-1 by CD44hi2W1S:I-Ab+CD4+ T cells. (E) Total number of CD44hi2W1S:I-Ab+CD4+ CXCR5+ PD-1+ TFH cells. (F) Enumeration of CD44hi2W1S:I-Ab+ CD4+ T cells from mice given Abs the day after challenge. (G) Immunofluorescence staining of spleen sections DAPI (grey) and expression of Bcl-6 (green), CD3 (blue) and CD4 (red) shown. Magnification 25×, scale bar represents 100 μm. Confocal images are representative of five mice. (H) Area of Bcl-6+ germinal centre (GC) per 1000 μm2 spleen. (I) Absolute number of GCs per 100 000 μm2 spleen. (A–C, E, H, I) Data are pooled from two independent experiments, each data point represents one mouse. Bars show medians. (D) Plots are representative of ≥6 mice pooled from two independent experiments. Mann–Whitney test, *p < 0.05, NS = non-significant.

Mentions: To further investigate whether OX40 signals were required for the formation of TFH cells in the response to Lm-2W, mice deficient in both OX40 and CD30 were used, since there may be redundancy in these signalling pathways 8. WT and CD30−/−OX40−/− mice were immunised with Lm-2W and then analysed at 7 dpi. An overall decrease in the number of CD44hi2W1S:I-Ab+CD4+ T cells (Supporting Information Fig. 2; p = 0.0317; median for WT: 52 331, CD30−/−OX40−/−: 21 975) resulted from less CXCR5− effector cells (p = 0.0159; median for WT: 27 164, CD30−/−OX40−/−: 8103) consistent with decreased survival, however generation of TFH was not impaired (p = 0.5556; median for WT: 2850, CD30−/−OX40−/−: 3430), indicating that the generation of these cells did not require OX40 signals.


OX40 controls effector CD4+ T-cell expansion, not follicular T helper cell generation in acute Listeria infection.

Marriott CL, Mackley EC, Ferreira C, Veldhoen M, Yagita H, Withers DR - Eur. J. Immunol. (2014)

Ligation of OX40 upon challenge enhances memory cell expansion and skews phenotype towards T effector memory. Secondary lymphoid tissues were analysed from mice receiving agonistic anti-OX40 or control IgG Abs after challenge. (A) Enumeration of CD44hi2W1S:I-Ab+CD4+ T cells given Abs on the day of challenge. Percentage of CD44hi2W1S:I-Ab+CD4+ T cells that are (B) CXCR5+PD-1+ TFH cells or (C) CXCR5−PD-1− effector cells. (D) Expression pattern of CXCR5 and PD-1 by CD44hi2W1S:I-Ab+CD4+ T cells. (E) Total number of CD44hi2W1S:I-Ab+CD4+ CXCR5+ PD-1+ TFH cells. (F) Enumeration of CD44hi2W1S:I-Ab+ CD4+ T cells from mice given Abs the day after challenge. (G) Immunofluorescence staining of spleen sections DAPI (grey) and expression of Bcl-6 (green), CD3 (blue) and CD4 (red) shown. Magnification 25×, scale bar represents 100 μm. Confocal images are representative of five mice. (H) Area of Bcl-6+ germinal centre (GC) per 1000 μm2 spleen. (I) Absolute number of GCs per 100 000 μm2 spleen. (A–C, E, H, I) Data are pooled from two independent experiments, each data point represents one mouse. Bars show medians. (D) Plots are representative of ≥6 mice pooled from two independent experiments. Mann–Whitney test, *p < 0.05, NS = non-significant.
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fig02: Ligation of OX40 upon challenge enhances memory cell expansion and skews phenotype towards T effector memory. Secondary lymphoid tissues were analysed from mice receiving agonistic anti-OX40 or control IgG Abs after challenge. (A) Enumeration of CD44hi2W1S:I-Ab+CD4+ T cells given Abs on the day of challenge. Percentage of CD44hi2W1S:I-Ab+CD4+ T cells that are (B) CXCR5+PD-1+ TFH cells or (C) CXCR5−PD-1− effector cells. (D) Expression pattern of CXCR5 and PD-1 by CD44hi2W1S:I-Ab+CD4+ T cells. (E) Total number of CD44hi2W1S:I-Ab+CD4+ CXCR5+ PD-1+ TFH cells. (F) Enumeration of CD44hi2W1S:I-Ab+ CD4+ T cells from mice given Abs the day after challenge. (G) Immunofluorescence staining of spleen sections DAPI (grey) and expression of Bcl-6 (green), CD3 (blue) and CD4 (red) shown. Magnification 25×, scale bar represents 100 μm. Confocal images are representative of five mice. (H) Area of Bcl-6+ germinal centre (GC) per 1000 μm2 spleen. (I) Absolute number of GCs per 100 000 μm2 spleen. (A–C, E, H, I) Data are pooled from two independent experiments, each data point represents one mouse. Bars show medians. (D) Plots are representative of ≥6 mice pooled from two independent experiments. Mann–Whitney test, *p < 0.05, NS = non-significant.
Mentions: To further investigate whether OX40 signals were required for the formation of TFH cells in the response to Lm-2W, mice deficient in both OX40 and CD30 were used, since there may be redundancy in these signalling pathways 8. WT and CD30−/−OX40−/− mice were immunised with Lm-2W and then analysed at 7 dpi. An overall decrease in the number of CD44hi2W1S:I-Ab+CD4+ T cells (Supporting Information Fig. 2; p = 0.0317; median for WT: 52 331, CD30−/−OX40−/−: 21 975) resulted from less CXCR5− effector cells (p = 0.0159; median for WT: 27 164, CD30−/−OX40−/−: 8103) consistent with decreased survival, however generation of TFH was not impaired (p = 0.5556; median for WT: 2850, CD30−/−OX40−/−: 3430), indicating that the generation of these cells did not require OX40 signals.

Bottom Line: Mice deficient in OX40 and CD30 showed normal generation of TFH cells but impaired numbers of 2W1S-specific effector cells.OX40 was not expressed by 2W1S-specific memory cells, although it was rapidly up-regulated upon challenge whereupon Ab-ligation of OX40 specifically affected the effector subset.In summary, these data indicate that for CD4(+) T cells, OX40 signals are important for generation of effector T cells rather than TFH cells in this response to acute bacterial infection.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Show MeSH
Related in: MedlinePlus