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A potential new pathway for PD-L1 costimulation of the CD8-T cell response to Listeria monocytogenes infection.

Xu D, Fu HH, Obar JJ, Park JJ, Tamada K, Yagita H, Lefrançois L - PLoS ONE (2013)

Bottom Line: However, PD-L1 can also act as a positive costimulator, but the relevant counterreceptor is not known.Simultaneous CD4-T cell depletion and anti-PD-L1 blockade revealed that PD-L1 provided costimulation even in the absence of CD4-T cells.Most importantly, specific blockade of PD-L1 binding to CD80 or to PD-1 did not recapitulate PDL-1 blockade.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, United States of America.

ABSTRACT
Programmed death ligand-1 (PD-L1) is an important negative regulator of T cell immune responses via interactions with PD-1 and CD80. However, PD-L1 can also act as a positive costimulator, but the relevant counterreceptor is not known. We analyzed the role of PD-L1 in CD8-T cell responses to infection with Listeria monocytogenes (LM) or vesicular stomatitis virus (VSV). PD-L1 blockade impaired antigen-specific CD8 effector T cell expansion in response to LM, but not to VSV infection, particularly limiting short-lived effector cell differentiation. Simultaneous CD4-T cell depletion and anti-PD-L1 blockade revealed that PD-L1 provided costimulation even in the absence of CD4-T cells. Most importantly, specific blockade of PD-L1 binding to CD80 or to PD-1 did not recapitulate PDL-1 blockade. The results suggested that PD-L1 plays an important costimulatory role for antigen-specific CD8 T cells during LM infection perhaps through a distinct receptor or interaction epitope.

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PD-L1 costimulation is independent of CD4 T cell help.A, Representative dot-plots of the antigen-specific CD8 T cell response eight days after LM-OVA infection following PD-L1 blocking with or without CD4 T cell depletion. B, The total numbers of OVA257–264/Kb-specific CD8 T cells or panel C, the total numbers of CD11ahigh CD8 T cells cells in the spleen from day 8 LM infected mice treated with IgG isotype control, anti-PD-L1 (10F.9G2), anti-CD4 (GK1.5), or both anti-PD-L1 and anti-CD4. Comparison of the magnitude of blocking between PD-L1 blockade with or without CD4 T cell depletion is shown under the bar graph in panel B. Data are representative of three independent experiments with five mice per group. ***p<0.001.
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pone-0056539-g007: PD-L1 costimulation is independent of CD4 T cell help.A, Representative dot-plots of the antigen-specific CD8 T cell response eight days after LM-OVA infection following PD-L1 blocking with or without CD4 T cell depletion. B, The total numbers of OVA257–264/Kb-specific CD8 T cells or panel C, the total numbers of CD11ahigh CD8 T cells cells in the spleen from day 8 LM infected mice treated with IgG isotype control, anti-PD-L1 (10F.9G2), anti-CD4 (GK1.5), or both anti-PD-L1 and anti-CD4. Comparison of the magnitude of blocking between PD-L1 blockade with or without CD4 T cell depletion is shown under the bar graph in panel B. Data are representative of three independent experiments with five mice per group. ***p<0.001.

Mentions: PD-L1 preferentially costimulated the CD8 T cell response with little effect on the CD4 T cell response (Fig. 2). Since the CD8 T cell response to LM is CD4 T cell dependent [24], we next tested whether PD-L1 operated independently or cooperatively with CD4 T cells to augment the CD8 T cell response. To test this, we blocked PD-L1 separately or in conjunction with CD4 T cell depletion. While both treatments inhibited the response, anti-PD-L1 blockade was somewhat more effective than CD4 depletion (Fig. 7A,B). However, CD4 T cell depletion together with anti-PD-L1 blockade substantially enhanced the inhibitory effect of either treatment alone. We further calculated the ratio of antigen-specific CD8 T cell numbers with or without PD-L1 blockade and CD4 T cell depletion. The level of inhibition was similar in the presence or absence of CD4 T cells (Fig. 7B). We noticed that the CD11a expression on tetramer-negative CD8 T cells appeared to increase after PD-L1 blockade or CD4 depletion (Fig. 7A). However, the total number of splenic CD11ahigh CD8 T cells was not different between the groups (Fig. 7C), suggesting that CD11a upregulation might be non-specific and the result of alterations in the inflammatory environment. Overall, these data indicated that both PD-L1 costimulation and CD4 T cell help were required for optimal CD8 T cell responses to LM infection.


A potential new pathway for PD-L1 costimulation of the CD8-T cell response to Listeria monocytogenes infection.

Xu D, Fu HH, Obar JJ, Park JJ, Tamada K, Yagita H, Lefrançois L - PLoS ONE (2013)

PD-L1 costimulation is independent of CD4 T cell help.A, Representative dot-plots of the antigen-specific CD8 T cell response eight days after LM-OVA infection following PD-L1 blocking with or without CD4 T cell depletion. B, The total numbers of OVA257–264/Kb-specific CD8 T cells or panel C, the total numbers of CD11ahigh CD8 T cells cells in the spleen from day 8 LM infected mice treated with IgG isotype control, anti-PD-L1 (10F.9G2), anti-CD4 (GK1.5), or both anti-PD-L1 and anti-CD4. Comparison of the magnitude of blocking between PD-L1 blockade with or without CD4 T cell depletion is shown under the bar graph in panel B. Data are representative of three independent experiments with five mice per group. ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569435&req=5

pone-0056539-g007: PD-L1 costimulation is independent of CD4 T cell help.A, Representative dot-plots of the antigen-specific CD8 T cell response eight days after LM-OVA infection following PD-L1 blocking with or without CD4 T cell depletion. B, The total numbers of OVA257–264/Kb-specific CD8 T cells or panel C, the total numbers of CD11ahigh CD8 T cells cells in the spleen from day 8 LM infected mice treated with IgG isotype control, anti-PD-L1 (10F.9G2), anti-CD4 (GK1.5), or both anti-PD-L1 and anti-CD4. Comparison of the magnitude of blocking between PD-L1 blockade with or without CD4 T cell depletion is shown under the bar graph in panel B. Data are representative of three independent experiments with five mice per group. ***p<0.001.
Mentions: PD-L1 preferentially costimulated the CD8 T cell response with little effect on the CD4 T cell response (Fig. 2). Since the CD8 T cell response to LM is CD4 T cell dependent [24], we next tested whether PD-L1 operated independently or cooperatively with CD4 T cells to augment the CD8 T cell response. To test this, we blocked PD-L1 separately or in conjunction with CD4 T cell depletion. While both treatments inhibited the response, anti-PD-L1 blockade was somewhat more effective than CD4 depletion (Fig. 7A,B). However, CD4 T cell depletion together with anti-PD-L1 blockade substantially enhanced the inhibitory effect of either treatment alone. We further calculated the ratio of antigen-specific CD8 T cell numbers with or without PD-L1 blockade and CD4 T cell depletion. The level of inhibition was similar in the presence or absence of CD4 T cells (Fig. 7B). We noticed that the CD11a expression on tetramer-negative CD8 T cells appeared to increase after PD-L1 blockade or CD4 depletion (Fig. 7A). However, the total number of splenic CD11ahigh CD8 T cells was not different between the groups (Fig. 7C), suggesting that CD11a upregulation might be non-specific and the result of alterations in the inflammatory environment. Overall, these data indicated that both PD-L1 costimulation and CD4 T cell help were required for optimal CD8 T cell responses to LM infection.

Bottom Line: However, PD-L1 can also act as a positive costimulator, but the relevant counterreceptor is not known.Simultaneous CD4-T cell depletion and anti-PD-L1 blockade revealed that PD-L1 provided costimulation even in the absence of CD4-T cells.Most importantly, specific blockade of PD-L1 binding to CD80 or to PD-1 did not recapitulate PDL-1 blockade.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, United States of America.

ABSTRACT
Programmed death ligand-1 (PD-L1) is an important negative regulator of T cell immune responses via interactions with PD-1 and CD80. However, PD-L1 can also act as a positive costimulator, but the relevant counterreceptor is not known. We analyzed the role of PD-L1 in CD8-T cell responses to infection with Listeria monocytogenes (LM) or vesicular stomatitis virus (VSV). PD-L1 blockade impaired antigen-specific CD8 effector T cell expansion in response to LM, but not to VSV infection, particularly limiting short-lived effector cell differentiation. Simultaneous CD4-T cell depletion and anti-PD-L1 blockade revealed that PD-L1 provided costimulation even in the absence of CD4-T cells. Most importantly, specific blockade of PD-L1 binding to CD80 or to PD-1 did not recapitulate PDL-1 blockade. The results suggested that PD-L1 plays an important costimulatory role for antigen-specific CD8 T cells during LM infection perhaps through a distinct receptor or interaction epitope.

Show MeSH
Related in: MedlinePlus