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The Journal of Immunology, 2008, 180, 7553 -7557
Copyright © 2008 by The American Association of Immunologists, Inc.
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PDL-1 Blockade Impedes T Cell Expansion and Protective Immunity Primed by Attenuated Listeria monocytogenes1

Jared H. Rowe, Tanner M. Johanns, James M. Ertelt and Sing Sing Way2

Departments of Pediatrics and Microbiology, Center for Infectious Disease and Microbiology Translational Research, University of Minnesota School of Medicine, Minneapolis, MN 55455


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Infection with attenuated Listeria monocytogenes (Lm) is a robust in vivo model for examining how Ag-specific T cells are primed, and subsequent challenge with virulent Lm allows for the protective effects of T cell priming to be quantified. Herein, we investigated the role of programmed death ligand 1 (PDL-1) in T cell priming and immunity conferred after primary infection with Lm {Delta}actA followed by virulent Lm challenge. In striking contrast to the inhibitory role of PDL-1 on T cell immunity in other infection models, marked reductions in the magnitude of T cell expansion and the kinetics of T cell proliferation were observed with PDL-1 blockade after primary Lm {Delta}actA infection. More importantly, PDL-1 blockade beginning before primary infection and maintained throughout the experiment resulted in delayed bacterial clearance and T cell expansion after secondary challenge with virulent Lm. These results indicate that for immunity to intracellular bacterial infection, PDL-1 plays an important stimulatory role for priming and expansion of protective T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Pprogrammed death ligand 1 (PDL-13; B7-H1) belongs to the B7 family of costimulatory molecules that also includes B7-1 (CD80), B7-2 (CD86), and B7-DC (CD273 or PDL-2) (1, 2). T cell engagement with each of these costimulatory receptors can confer both stimulatory and inhibitory signals, and the overall magnitude of the Ag-specific T cell response after immunization or infection is controlled by multiple T cell activation and suppression signals. Therefore, understanding how these various opposing signals together control Ag-specific T cell activation is required for the more rational design of vaccines that aim to target T cell-mediated immunity. Although PDL-1 can provide both T cell inhibitory and activation signals, as examined with both in vitro models of T cell activation and in vivo models of autoimmune disease, functional studies with in vivo infection models have uniformly demonstrated that T cell stimulation by PDL-1 suppresses T cell proliferation and effector function (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13). For example, during chronic lymphocytic choriomeningitis virus (LCMV) infection, in vivo PDL-1 blockade restores proliferation and cytolytic function to virus-specific "exhausted" CD8 T cells and results in viral clearance (6). Similarly, PDL-1 blockade restores activation and proliferation to virus-specific T cells during both chronic hepatitis B and acute herpes simplex virus in mouse infection models (7, 9), as well as proliferation and cytolytic function for HIV-specific or hepatitis C virus-specific CD8 T cells from human patients with these chronic infections (10, 11, 12). Accordingly, reinvigorating viral T cells through PDL-1 blockade has been proposed as a novel therapeutic intervention for treatment of chronic viral infection.

Listeria monocytogenes (Lm) is an intracellular Gram-positive bacterium that primarily causes localized infections in the gastrointestinal tract in immune-competent individuals, and more severe systemic infections in immune-compromised individuals. During infection, Lm primes a robust Ag-specific CD8 and CD4 T cell response, and accordingly Lm infection is a widely used experimental model whereby priming and activation of Ag-specific T cells and the protective effects of these T cells are examined (14). Furthermore, because of the relative ease by which recombinant Lm strains can be generated, as well as the existence of many highly attenuated and immunogenic Lm mutant strains, recombinant Lm expressing protective Ags from other pathogens are being explored as a new class of live attenuated vaccine vectors (15, 16, 17). In this study we examined the effects of PDL-1 blockade on T cell priming and expansion after primary infection with Lm {Delta}actA, and of protective immunity following secondary challenge with virulent Lm. The highly attenuated nature of Lm {Delta}actA compared with wild-type Lm normalizes Ag load after primary infection, thereby bypassing potential difference in innate susceptibility between groups of mice, allowing for a more accurate comparison of the resulting T cell response (18, 19, 20, 21). In this report, we first demonstrate that PDL-1 expression is markedly up-regulated during Lm {Delta}actA primary infection, and that PDL-1 blockade does not alter Ag load or the kinetics of bacterial clearance following infection with this attenuated Lm strain. Additional studies using Lm {Delta}actA primary infection to normalize initial Ag load between anti-PDL-1 Ab- and control Ab-treated mice demonstrate that PDL-1 blockade delays the kinetics of T cell priming and reduces the magnitude of T cell expansion after primary Lm {Delta}actA infection. Importantly, PDL-1 blockade beginning before T cell priming and maintained throughout secondary challenge reveals an important role for PDL-1 in optimal bacterial clearance and secondary T cell expansion after challenge with virulent Lm.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice

C57B6 (H-2Kb) female mice were purchased from the National Cancer Institute and used at 6–8 wk of age. OT-1 TCR transgenic mice have been described and were intercrossed with CD90.1 mice and maintained on a RAG-1-deficient background (22). All experiments were performed under University of Minnesota Institutional Animal Care and Use Committee approved protocols.

Listeria monocytogenes

The recombinant Lm strain Lm-OVA and Lm-OVA {Delta}actA derived through targeted deletion in the actA gene were used allowing for an analysis of the immune response to the surrogate Lm-specific H-2Kb OVA257–264 Ag as described (20, 22). For infections, Lm were grown to early log phase (OD600 of 0.1) in brain heart infusion medium at 37°C, washed, and diluted with saline to 200 µl final volume and injected i.v. At the indicated time points after infection, the numbers of recoverable bacteria in the organs of infected mice were quantified by homogenization in saline containing Triton X (0.05%), and plating serial dilutions of the homogenate on brain heart infusion plates was as described (21, 23).

Reagents for in vitro cultures, cell staining, and adoptive transfer

For in vivo PDL-1 blockade, anti-mouse PDL-1 (clone 10F.9G2) or rat IgG2b isotype control (clone LTF-2) Abs (6, 9) were purchased from BioExpress and injected i.p. in the following manner: 1 day before primary infection (500 µg/mouse), days 4 and 8 after primary infection, and day 1 before rechallenge (250 µg/mouse). The CD8 T cell response to OVA257–264 was examined with H-2Kb dimer X loaded with OVA257–264 peptide according to the manufacturer's instructions (BD Biosciences). Abs for cell surface staining and reagents for intracellular cytokine and annexin V staining were purchased from BD Biosciences and used according to the manufacturer's recommendations. For in vitro culture, splenocytes were plated into 96-well round-bottom plates (5 x 106 cells/ml) and stimulated with the indicated peptides (10–6 M) with brefeldin A (BD GolgiPlug reagent from BD Biosciences) for 5 h as described (20). For adoptive transfer, 105 CD8 T cells from OT-1 (CD90.1) mice were CFSE labeled (5 µM final concentration) and transferred i.v. into recipient mice 1 day before Lm infection.

Statistics

The differences in number and percentage of Ag-specific cells, as well as geometric mean CFUs between groups of mice, were evaluated by using Student's t test with p < 0.05 taken as statistically significant (GraphPad Prism software).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
PDL-1 expression after primary Lm {Delta}actA infection

Although expressed constitutively on most lymphoid cells, PDL-1 expression is up-regulated on virtually all splenocytes during chronic viral infection (6). Functionally, PDL-1 expression during chronic viral infection actively suppresses virus-specific CD8 T cells because PDL-1 blockade restores the function of virus-specific exhausted T cells into "effector" cells capable of viral clearance (6). To gain insight into how and when PDL-1 may alter T cell priming during acute bacterial infection, we examined the kinetics of PDL-1 expression on splenocytes after primary Lm infection. Remarkably, beginning 24 h after infection with 106 CFUs of Lm {Delta}actA, PDL-1 was up-regulated on the majority of all splenocytes (Fig. 1). At this time point, the level of PDL-1 expression was highest among the CD11c+ splenocyte population, consistent with the important role this subset of APCs plays in T cell priming after Lm infection (24). PDL-1 was also dramatically up-regulated on other splenocyte subpopulations including CD11b+, B220+, CD4+, and CD8+ cells. PDL-1 up-regulation in response to Lm {Delta}actA infection was maintained through day 3, dramatically reduced by day 6, and returned to levels present in naive mice on day 14 after infection. The kinetics for PDL-1 up-regulation and return to baseline on CD11c+ cells were similar to the expression kinetics of other molecules important for T cell priming such as CD80, CD86, MHC class I (H-2Kb), and MHC class II (I-Ab) (Fig. 1 and data not shown).


Figure 1
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  		FIGURE 1. PDL-1, CD80, and CD86 expression among all splenocytes or specific splenocyte cell subsets at the indicated time points after infection with 106 Lm {Delta}actA (open histograms) compared with no infection mice (shaded histograms). These data are from 2 mice per experimental group per time point and are representative of three independent experiments with similar results.

 
PDL-1 blockade reduces Ag-specific T cell expansion after primary Lm {Delta}actA infection

To evaluate the overall role of PDL-1 in T cell priming that accommodates the brisk nature whereby PDL-1 is up-regulated during Lm infection, we pretreated mice with either anti-PDL-1 blocking or isotype control Ab beginning 1 day before infection. Remarkably, in vivo PDL-1 blockade effectively blocked access to both constitutive levels of cell surface PDL-1 and the increased expression levels present after infection because only background levels of PDL-1 staining could be detected in anti-PDL-1-treated mice (Fig. 2A). These reductions were specific to PDL-1 because anti-PDL-1 blockade did not alter the cell surface expression of other costimulation molecules in response to Lm infection (Fig. 2A). Other experiments indicate that PDL-1 blockade does not alter the Ag load or kinetics of bacterial clearance after Lm-OVA {Delta}actA infection because the numbers of recoverable CFUs are virtually identical at early time points (24, 48, and 72 h) after infection between anti-PDL-1-treated and control mice (Fig. 2B). In this experimental model beginning day 5 after Lm {Delta}actA infection, an ~70% reduction in the Ag-specific CD8 T cell response enumerated by OVA257–264 dimer staining was present for anti-PDL-1-treated compared with control mice (p < 0.001) (Fig. 3A). This reduced magnitude Ag-specific CD8 T cell response was maintained through the peak (day 8) and contraction phase (days 15–30) of the T cell response. Similarly during the peak T cell response, there was an ~70% reduction in the number of Ag-specific CD8 T cells in splenocytes from anti-PDL-1-treated compared with control mice (Fig. 3B). Moreover, 50–70% reductions in both the percentage and total number of cytokines producing CD8 and CD4 T cells among splenocytes were present after stimulation with the MHC class I peptide OVA257–264 or MHC class II peptide LLO189–201, respectively (Fig. 3, C and D). These results indicate that PDL-1 blockade impedes Ag-specific T cell expansion after primary Lm {Delta}actA infection.


Figure 2
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  		FIGURE 2. A, PDL-1 and CD80 expression among all splenocytes (top panels) or CD11c+ splenocyte cells (bottom panels) from mice 3 days after infection with 106 Lm {Delta}actA (open histograms) or no infection (shaded histograms) treated with either rat IgG2b isotype control or anti-PDL-1 Ab before infection. These data are from 2 mice per experimental group per time point and are representative of three independent experiments. B, Number of recoverable Lm CFUs per spleen in rat IgG2b control (shaded bars) or anti-PDL-1 Ab- (open bars) treated mice at the indicated time points after infection. These data are from 4–5 mice per group and are reflective of two independent experiments. Bar, SE.

 

Figure 3
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  		FIGURE 3. A, Percentage of Ag-specific CD8 T cells among PBMCs in anti-PDL-1 Ab-treated and control mice at the indicated time points after infection with 106 Lm {Delta}actA quantified by H-2Kb OVA257–264 dimer staining. B, Number of H-2Kb OVA257–264 dimer+ CD8 T cells among splenocytes on day 8 post-infection. C, Percentage and number of IFN-{gamma} producing CD8 T cells among splenocytes after stimulation with OVA257–264 peptide or no stimulation on day 8 post-infection. D, Percentage and number of IFN-{gamma} producing CD4 T cells among splenocytes after LLO189–201 peptide stimulation on day 8 post-infection. These data represent 7–12 mice per experimental group and are representative of three independent determinations. Bar, SE. *, p < 0.05.

 
PDL-1 blockade impedes Ag-specific T cell priming

Early priming events after Lm infection play critical roles regulating both the kinetics and magnitude of the Ag-specific T cell response (19). To determine whether reductions in T cell expansion resulting from PDL-1 blockade are due to defects in early T cell priming, we examined the degree of proliferation and magnitude of expansion in adoptively transferred Ag-specific T cells in the first few days following Lm {Delta}actA infection. Beginning at 48 h after infection, adoptively transferred Ag-specific OT-1 CD8 (CD90.1) T cells could be readily detected, and at this early time point consistent reductions were present in both cell number and degree of CFSE dilution among Ag-specific T cells adoptively transferred into anti-PDL-1-treated compared with control mice (Fig. 4A). Reduced levels of CFSE dilution and expansion among Ag-specific T cells in anti-PDL-1 Ab treated compared with control mice became more pronounced by day 3 after infection (Fig. 4A). By day 4 after infection, when CFSE was fully diluted among transferred cells in both groups of mice, significant reductions in both percentage and total numbers of Ag-specific OT-1 cells in mice treated with anti-PDL-1 compared with control Ab were still present (Fig. 4B). In similar experiments, we evaluated the possibility that reduced numbers of Ag-specific T cells present in anti-PDL-1-treated compared with control mice were the result of increased apoptotic cell death, because in other systems, direct stimulation of activated human T cells with immobilized anti-PDL-1 Ab in vitro can lead to increased rates of apoptotic cell death (25). These experiments revealed no difference in annexin V staining among Ag-specific OT-1 cells recovered from anti-PDL-1-treated and control mice (Fig. 4C), and they indicate that potential differences in the rate of apoptotic cell death attributable to anti-PDL-1 Ab in other systems do not contribute significantly to observed reductions in the number of Ag-specific T cells primed after Lm infection. Taken together, these results indicate that after primary Lm {Delta}actA infection, PDL-1 blockade interferes with early events in T cell priming, resulting in reduced proliferation and expansion of Ag-specific T cells.


Figure 4
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  		FIGURE 4. A, Expansion and CFSE dilution in adoptively transferred OT-I (CD90.1+CD8+) cells at the indicated time points after infection with 106 Lm {Delta}actA in anti-PDL-1 Ab-treated (gray histograms), control rat IgG2b-treated (open histograms), or no infection control mice (black histograms). The numbers in the upper left quadrant indicate percentage of gated cells among total splenocytes. B, Number of OT-I (CD90.1+CD8+) per mouse spleen before infection and day 4 after infection in anti-PDL-1 Ab- (gray circle) or rat IgG2b Ab- (filled square) treated mice. C, Annexin V staining among OT-1 (CD90.1+CD8+) cells day 3 after infection in either anti-PDL-1-treated (gray histograms) or control IgG2b-treated (open histograms) mice. These data represent 5–7 mice for each experimental group combined from two independent experiments. Bar, SE.

 
PDL-1 blockade delays bacterial clearance after challenge with virulent Lm

To evaluate the overall impact that PDL-1 plays in protective immunity primed by attenuated Lm infection, we examined the susceptibility of anti-PDL-1 Ab-treated and control mice to challenge with an inocula of virulent Lm lethal for naive mice (1 LD50). Consistent with other studies demonstrating the remarkable efficiency whereby prior infection with Lm {Delta}actA primes protective T cell immunity allowing virulent Lm to be rapidly cleared after challenge (18), there were ~4 log-fold reductions in recoverable Lm CFUs in the livers by day 3 after challenge for Lm {Delta}actA-primed compared with naive control mice with each treated with isotype control Ab (Fig. 5A). However, the degree of protection primed with Lm {Delta}actA was significantly reduced by PDL-1 blockade because ~2 log-fold increased numbers of Lm were present for anti-PDL-1 Ab-treated compared with control mice (p = 0.001). Moreover, this is likely an underrepresentation of the true difference between these groups because 4 of 7 control mice (rat IgG2b treated) had Lm CFUs below the limits of detection, while Lm CFUs were present for all anti-PDL-1-treated mice (7 total). To evaluate whether the increased susceptibility to virulent Lm challenge for anti-PDL-1-treated compared with control mice reflects either a failure or delay in bacterial clearance, Lm CFUs were also examined at additional later time points. By day 5 after challenge, the numbers of recoverable Lm for both anti-PDL-1 Ab-treated and control mice were below the limits of detection (Fig. 5A). These results indicate that PDL-1 blockade delays bacterial clearance after secondary challenge with virulent Lm.


Figure 5
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  		FIGURE 5. A, Numbers of recoverable Lm CFUs in the liver days 3 and 5 after challenge with 105 virulent Lm for the indicated groups of naive mice (solid bar) or mice previously inoculated with Lm {Delta}actA 30 days before challenge (shaded bars). For these experiments, mice were treated with either anti-PDL-1 or control Ab before primary infection, and throughout the experiment as described in the Materials and Methods. B, Number of IFN-{gamma} producing CD8 T cells after stimulation with OVA257–264 peptide among splenocytes before challenge (day 30 after Lm {Delta}actA infection), and days 3 and 5 after challenge with virulent Lm. These data represent 7 mice for each experimental group combined from two independent experiments. Bar, SE. *, p < 0.05.

 
Lastly, we examined the role of PDL-1 in Ag-specific T cell expansion after secondary infection by enumerating the Ag-specific T cell response to OVA257–264 before challenge (day 30 after Lm {Delta}actA primary infection) and days 3 and 5 after secondary challenge with virulent Lm (Fig. 5B). Consistent with the marked reductions in T cell expansion after primary infection with Lm {Delta}actA attributable to PDL-1 blockade, significantly delayed kinetics and reductions in overall magnitude of T cell expansion after secondary challenge with virulent Lm were observed for anti-PDL-1 Ab-treated compared with control mice. Taken together, these results indicate that PDL-1 blockade impedes Ag-specific T cell priming and protective immunity during Lm infection.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
PDL-1 T cell stimulation uniformly results in suppression of pathogen-specific T cell proliferation and effector function after evaluation in various in vivo infection models (6, 7, 8, 9, 10, 11, 12). However, whether PDL-1-mediated suppression of Ag-specific T cell proliferation is beneficial or detrimental for the host appears to be pathogen and context dependent. For LCMV clone 13 and other viruses that cause chronic infection, active T cell inhibition through PDL-1 results in Ag-specific T cells that are phenotypcially exhausted and cannot eradicate virus, resulting in chronic infection (6, 8, 9, 10, 11, 12). In contrast, for acute HSV-1 infection causing stromal keratitis, PDL-1-mediated suppression of virus-specific T cell priming and apoptosis limits the severity of disease caused by activated T cells (7). Herein, we report experimental data demonstrating a stimulatory role for PDL-1 in T cell proliferation and expansion, as well as a protective role for PDL-1 using an in vivo priming model of protective immunity to Lm infection.

First, we demonstrate the marked up-regulation of PDL-1 expression from baseline levels on virtually all immune cells after Lm infection, with CD11c+ having the highest levels of expression. The role of PDL-1 expression in priming T cell immunity after Lm infection was examined treating mice with either anti-PDL-1 blocking or control Ab before and during infection. To bypass potential roles that PDL-1 may play in innate resistance to virulent Lm infection leading to differences in Lm Ag load, infection with the {Delta}actA Lm mutant was used. This highly attenuated Lm lacks the bacterial virulence protein necessary for actin recruitment and intracellular and intercellular spread and therefore is rapidly cleared, even in mice lacking key components of innate resistance (18, 20, 21). Similarly, we now demonstrate that infection with Lm {Delta}actA normalize Ag load in anti-PDL-1-treated and control mice at early time points when potential differences can critically affect the immune response magnitude (19). Using this in vivo model to prime Lm-specific T cells, we demonstrate consistent ~70% reductions in the Ag-specific T cell response for anti-PDL-1 Ab-treated compared with control mice quantified using both MHC multimer and intracellular cytokine staining techniques. Additional experiments using adoptively transferred Ag-specific T cells from TCR transgenic mice indicate that PDL-1 plays an important role in early T cell priming because cells recovered from anti-PDL-1-treated compared with control mice had delayed CFSE dilution and decreased overall expansion. Importantly, after challenge with virulent Lm in mice primed with Lm {Delta}actA, PDL-1 blockade throughout the experiment led to delayed bacterial clearance and secondary expansion of Ag-specific T cells.

Therefore, during Lm infection, unlike the other previously described in vivo infection models, PDL-1 is required for optimal T cell proliferation and expansion. These results are consistent with the stimulatory role for PDL-1 previously described in other noninfectious in vivo and in vitro models of T cell activation (3, 4, 5). Our results demonstrating that PDL-1 stimulates T cell immunity after primary infection with Lm {Delta}actA are also consistent with a recent study describing a defect in Lm-specific CD8 T cell expansion after infection with wild-type Lm using a different anti-PDL-1 blocking Ab and a different mouse strain (26). In this study, the increased susceptibility conferred by PDL-1 blockade to primary wild-type Lm infection was also demonstrated, underscoring the importance of using attenuated Lm for primary infection to normalize Ag load at early time points when the resulting adaptive T cell response is being evaluated. This critical difference or potentially other intrinsic differences between the two experimental systems led these authors to miss the important functional consequence of PDL-1 blockade that results in delayed bacterial clearance after rechallenge with virulent Lm that we now report. These results collectively challenge the dogma that T cell stimulation through PDL-1 during infection results in decreased proliferation and suppression of effector function, and instead demonstrates that the role of PDL-1 in T cell immunity is context dependent and varies with the type of infection. Determining the molecular basis for how T cell stimulation through PDL-1 and other costimulation signals can result in such drastic differences in proliferation and functional capacity during specific infections is an important area for future investigation.


   Acknowledgments
 
We thank Drs. Stephen McSorley, David Masopust, and Vaiva Vezys and members of their respective laboratories for helpful discussions.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflicts of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Funding was received from the following sources: NICHD/NIH-K08HD51584, Infectious Disease Society of America, March of Dimes Foundation, and Vikings Children's Fund. Back

2 Address correspondence and reprint requests to Dr. Sing Sing Way, 2001 6th Street SE, Room 3–212, Minneapolis, MN 55455. E-mail address: singsing{at}umn.edu Back

3 Abbreviations used in this paper: PDL-1, programmed death ligand 1; LCMV, lymphocytic choriomeningitis virus; Lm, Listeria monocytogenes. Back

Received for publication February 4, 2008. Accepted for publication March 23, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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