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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 facilitates SLEC differentiation.Eight days after LM-OVA infection, SLEC, MPEC, DPEC and EEC population was analyzed within OVA257–264/Kb+ splenic CD8 T cell population according to their KLRG1 and IL-7R expression. A, representative plots of the OVA-specific CD8 T cell response and the expression of CD127 and KLRG1 by gated tetramer+ cells with or without PD-L1 blockade. B, Graphs show the compiled proportion of each subset with or without anti-PD-L1 blockade (SLEC: KLRG1+ IL-7R-; MPEC: KLRG1−, IL−7R+; EEC: KLRG1−, IL−7R−; DPEC: KLRG1+, IL−7R+). Data are representative of three independent experiments with five mice per group. (*p<0.05, **p<0.01, ***p<0.001, ns, not significant).
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pone-0056539-g004: PD-L1 costimulation facilitates SLEC differentiation.Eight days after LM-OVA infection, SLEC, MPEC, DPEC and EEC population was analyzed within OVA257–264/Kb+ splenic CD8 T cell population according to their KLRG1 and IL-7R expression. A, representative plots of the OVA-specific CD8 T cell response and the expression of CD127 and KLRG1 by gated tetramer+ cells with or without PD-L1 blockade. B, Graphs show the compiled proportion of each subset with or without anti-PD-L1 blockade (SLEC: KLRG1+ IL-7R-; MPEC: KLRG1−, IL−7R+; EEC: KLRG1−, IL−7R−; DPEC: KLRG1+, IL−7R+). Data are representative of three independent experiments with five mice per group. (*p<0.05, **p<0.01, ***p<0.001, ns, not significant).

Mentions: Effector T cell heterogeneity is a hallmark of CD8 T cell responses to infections [21]. Based on KLRG1 and IL-7R expression levels, four populations of effector cells can be identified: early effector cells (KLRG1- IL-7R-; EEC) that give rise to the other subsets, short-lived effector cells (KLRG1+ IL-7R-; SLEC) that do not survive long-term, memory precursor effector cells (KLRG1− IL-7R+; MPEC) that survive to form the memory pool, and double positive effector cells (KLRG1+ IL−7R+; DPEC) whose origin is unclear [22]. A number of factors have been identified that affect the lineage decision toward MPEC vs. SLEC development [21], [23]. We therefore examined whether PD-L1 played a role in effector subset development in response to LM infection. Blockade of PD-L1 resulted in a decrease in all effector subsets with the greatest effect on SLEC generation (Fig. 4A,B). Moreover, blockade of PD-L1 during LM infection impaired bacterial clearance, while PD-1 blockade enhanced bacterial clearance in the spleen and liver (Fig. 5). This finding further indicated distinct functions for PD-1 and PD-L1 during the anti-LM response.


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 facilitates SLEC differentiation.Eight days after LM-OVA infection, SLEC, MPEC, DPEC and EEC population was analyzed within OVA257–264/Kb+ splenic CD8 T cell population according to their KLRG1 and IL-7R expression. A, representative plots of the OVA-specific CD8 T cell response and the expression of CD127 and KLRG1 by gated tetramer+ cells with or without PD-L1 blockade. B, Graphs show the compiled proportion of each subset with or without anti-PD-L1 blockade (SLEC: KLRG1+ IL-7R-; MPEC: KLRG1−, IL−7R+; EEC: KLRG1−, IL−7R−; DPEC: KLRG1+, IL−7R+). Data are representative of three independent experiments with five mice per group. (*p<0.05, **p<0.01, ***p<0.001, ns, not significant).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569435&req=5

pone-0056539-g004: PD-L1 costimulation facilitates SLEC differentiation.Eight days after LM-OVA infection, SLEC, MPEC, DPEC and EEC population was analyzed within OVA257–264/Kb+ splenic CD8 T cell population according to their KLRG1 and IL-7R expression. A, representative plots of the OVA-specific CD8 T cell response and the expression of CD127 and KLRG1 by gated tetramer+ cells with or without PD-L1 blockade. B, Graphs show the compiled proportion of each subset with or without anti-PD-L1 blockade (SLEC: KLRG1+ IL-7R-; MPEC: KLRG1−, IL−7R+; EEC: KLRG1−, IL−7R−; DPEC: KLRG1+, IL−7R+). Data are representative of three independent experiments with five mice per group. (*p<0.05, **p<0.01, ***p<0.001, ns, not significant).
Mentions: Effector T cell heterogeneity is a hallmark of CD8 T cell responses to infections [21]. Based on KLRG1 and IL-7R expression levels, four populations of effector cells can be identified: early effector cells (KLRG1- IL-7R-; EEC) that give rise to the other subsets, short-lived effector cells (KLRG1+ IL-7R-; SLEC) that do not survive long-term, memory precursor effector cells (KLRG1− IL-7R+; MPEC) that survive to form the memory pool, and double positive effector cells (KLRG1+ IL−7R+; DPEC) whose origin is unclear [22]. A number of factors have been identified that affect the lineage decision toward MPEC vs. SLEC development [21], [23]. We therefore examined whether PD-L1 played a role in effector subset development in response to LM infection. Blockade of PD-L1 resulted in a decrease in all effector subsets with the greatest effect on SLEC generation (Fig. 4A,B). Moreover, blockade of PD-L1 during LM infection impaired bacterial clearance, while PD-1 blockade enhanced bacterial clearance in the spleen and liver (Fig. 5). This finding further indicated distinct functions for PD-1 and PD-L1 during the anti-LM response.

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