Microbial Pathogenesis 80 (2015) 1-6

Programmed death ligand-1 expression and memory T-cell generation in Coxiella burnetii infection.

 

Ka MB1, Bechah Y2, Olive D3, Mege JL4.

1Aix-Marseille University, Unité de Recherche sur les Maladies Infectious Transmissible et Emergentes, UMR 63, CNRS 7278, IRD 198, INSERM U1095, Marseille, France; Inserm UMR 1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France.

2Aix-Marseille University, Unité de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, UMR 63, CNRS 7278, IRD 198, INSERM U1095, Marseille, France.

3Inserm UMR 1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France.

4Aix-Marseille University, Unité de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, UMR 63, CNRS 7278, IRD 198, INSERM U1095, Marseille, France. Electronic address:

 

Abstract

The regulation of T cells responses requires co-signaling molecules such as Programmed death ligand-1 (PD-L1) also called CD272 that interacts with PD-1. If the interaction PD-L1-PD1 plays a role in antitumoral immunity, its contribution to antibacterial defense is not well understood. The objective of our study was to determine the role of PD-L1 in Q fever, a zoonosis due to Coxiella burnetii, an intracellular organism. The patients with Q fever were stratified into individuals with primary infection and those developing endocarditis, a chronic evolution of the disease. The expression of PD-L1 at T cell surface was specifically increased in patients from the former group but not from the latter. Our hypothesis was that PD-L1 plays a role in the early phases of C. burnetii infection and we tested the hypothesis with a murine model of infection. C. burnetii infection resulted in PD-L1 up-regulation in splenocytes. The injection of neutralizing anti-PD-L1 antibodies to mice increased the bacterial load in spleen, modified the relative number of CD4+ T-cells compared with CD8+ T-cells and increased the proportion of splenic CD4+ and CD8+ T cells expressing low membrane CD62L levels. Our results indicate that PD-L1 affects bacterial clearance and interferes with T-cell activation, opening new perspectives in the understanding of Q fever pathophysiology.

KEYWORDS: CD62L; Coxiella burnetii; PD-L1; T-cells

PMID: 25680834

 

Supplement: 

Q fever is a zoonosis caused by Coxiella burnetii, an intracellular bacterium known to replicate in myeloid cells. During the primary infection, symptomatic patients present with fever, hepatitis or pneumonia [1]. Q fever control depends on granuloma formation and antigen-stimulated gamma interferon (IFN-γ) production even if the role of this canonical cytokine has to be reappraised. Q fever may become chronic in at risk patients and its major clinical manifestation is an endocarditis; this latter is characterized by defective immune response related to interleukin (IL)-10 overproduction [1, 2]. The adaptive immune response to pathogens involves TCR, co-stimulatory and/or co-inhibitory molecules. Among the co-inhibitory molecules, programmed death ligand (PD-L)-1, a member of the B7 family, plays an important role in the control of T-cell functions [3]. PD-L1 blockade induces effector T-cell activation [4]. The role of PD-L1 has been demonstrated in cancer progression, autoimmunity and graft rejection [5], but its role in infections is not well known. In Listeria monocytogenes-infected mice, PD-L1 engagement enhances the protective T-cell response and bacterial clearance. The role of PD-L1 in other bacterial infections remains to be determined.

We hypothesized that PD-L1 is involved in Q fever. We found that the expression of PD-L1 by CD4+ and CD8+ T-cells (Fig. 2) was significantly (P < 0.05) higher in patients with primary infection than in controls, but was similar in patients with Q fever endocarditis and controls. This finding suggests that PD-L1 might be involved in the early stage of C. burnetii infection. To test the hypothesis, we infected C57BL/6 mice with C. burnetii via the intraperitoneal route and determined the level of PD-L1 expression by splenocytes using flow cytometry (Fig. 1). We clearly observed that PD-L1 expression by splenocytes was increased as in patients with primary infection. To demonstrate a role of PD-L1 in C. burnetii infection, mice were treated with neutralizing anti-PD-L1 Abs before being infected.

 

JLM FIG1

Figure 1: LSR II cytometer

 

PD-L1 blockade significantly (P < 0.05) decreased bacterial load in spleen from C. burnetii infected mice. We wondered if the increase in bacterial clearance was related to the activation of T cells. We investigated CD62L expression a marker expressed on naïve CD4+ T-cells and CD8+ T-cells. In the mice treated with anti-PD-L1 mAbs before C. burnetii infection, approximately 80% of the CD4+ T-cells and 90% of the CD8+ T-cells expressed low levels of CD62L, suggesting that these T-cells were memory T-cells. In the mice treated with anti-PD-L1 mAbs and infected with C. burnetii, the proportion of T cells with low expression of CD62L decreased, suggesting that PDL-1 controls the frequency of naïve and memory T cells in C. burnetii infection.

Importance of the study: our data suggest that PD-L1 is an early marker of Coxiella burnetii infection and suggests an important role of inhibitory molecules in infectious disease.

 

 

JLM FIG2

Figure 2: Gating strategy. CD4 and CD8 T cells was gated on CD3+ T cells after exclusion of death cells and doublet.

 

References

[1] D. Raoult, T. Marrie, J.L. Mege, Natural history and pathophysiology of Q fever, Lancet Infect. Dis. 5 (2005) 219e226.

[2] C. Capo, J.L. Mege, Role of innate and adaptive immunity in the control of Q fever, Adv. Exp. Med. Biol. 984 (2012) 273e286.

[3] L. Chen, Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity, Nat. Rev. Immunol. 4 (2004) 336e347.

[4] Y.E. Latchman, S.C. Liang, Y. Wu, T. Chernova, R.A. Sobel, M. Klemm, et al., PDL1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 10691e10696.

[5] C. Blank, A. Mackensen, Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion, Cancer Immunol. Immunother. 56 (2007) 739e745.

 

FIG3Contact:

Ka Mignane

PhD Postdoctoral Associate

Aix-Marseille University, Unité de Recherche sur les Maladies Infectious Transmissible et Emergentes, UMR 63, CNRS 7278, IRD 198, INSERM U1095, Marseille, France.

Present adress : University of Pittsburgh School of Medicine Hillman Cancer Center, Research Pavilion 5117 Centre Avenue Pittsburgh, PA 15213

E-mail:kamb@upmc.edu

 

 

 

 

 

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