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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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Related in: MedlinePlus

PD-L1 costimulation augments protection against LM infection.Mice were infected with 1×105 cfu LM-OVA i.v. and treated with anti-PD-L1, anti-PD1 or control IgG. The bacterial burden in spleen and liver was analyzed five days later. Data are representative of two independent experiments with ten mice per group. Data were analyzed by Mann-Whitney test. (*p<0.05, **p<0.01, ns, not significant).
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pone-0056539-g005: PD-L1 costimulation augments protection against LM infection.Mice were infected with 1×105 cfu LM-OVA i.v. and treated with anti-PD-L1, anti-PD1 or control IgG. The bacterial burden in spleen and liver was analyzed five days later. Data are representative of two independent experiments with ten mice per group. Data were analyzed by Mann-Whitney test. (*p<0.05, **p<0.01, 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 augments protection against LM infection.Mice were infected with 1×105 cfu LM-OVA i.v. and treated with anti-PD-L1, anti-PD1 or control IgG. The bacterial burden in spleen and liver was analyzed five days later. Data are representative of two independent experiments with ten mice per group. Data were analyzed by Mann-Whitney test. (*p<0.05, **p<0.01, ns, not significant).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056539-g005: PD-L1 costimulation augments protection against LM infection.Mice were infected with 1×105 cfu LM-OVA i.v. and treated with anti-PD-L1, anti-PD1 or control IgG. The bacterial burden in spleen and liver was analyzed five days later. Data are representative of two independent experiments with ten mice per group. Data were analyzed by Mann-Whitney test. (*p<0.05, **p<0.01, 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