Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4+ T Effector and Regulatory T Cells in Cutaneous Leishmaniasis

Abstract

Cutaneous Leishmaniasis (CL) affects up to one million people every year and treatments are costly and toxic. The regulation of the host immune response is complex and the knowledge of how CD4 + T cells are activated and maintained during Leishmania infection is still limited. Current therapies aim to target programmed cell death (PD)-1 and programmed cell death ligand (PD-L)-1 in order to boost T cell activity. However, the role of the PD-1/PD-L1 axis during Leishmania infection is still unclear. In this study, we found that patients with active and post-treatment CL displayed different subsets of CD4 + PD-1 + T cells. Accordingly, L. major-infected mice upregulated PD-1 on activated CD4 + T effector cells and PD-L1 on resident macrophages and infiltrating monocytes at the site of infection. L. major-infected Pdl1 −/− mice expressed lower levels of MHCII and higher levels of CD206 on macrophages and monocytes and, more importantly, the lack of PD-L1 contributed to a reduced frequency of CD4 + Ly6C hi T effector cells and an increase of CD4 + Foxp3 + regulatory T cells at the site of infection and in draining lymph nodes. Additionally, the lack of PD-L1 was associated with lower production of IL-27 by infiltrating monocytes and lower levels of the Th1 cytokines IFN-γ and TNF-α produced by CD4 + T effector cells. Pdl1 −/− mice initially exhibited larger lesions despite having a similar parasite load. Our results describe for the first time how the interruption of the PD-1/PD-L1 axis influences the immune response against CL and suggests that this axis regulates the balance between CD4 + Ly6C hi T effector cells and CD4 + Foxp3 + regulatory T cells.

Unraveling the Role of Immune Checkpoints in Leishmaniasis

“…However, particularly in this study, other exhaustion markers have not been extensively investigated and this could give a better idea on the level of CD8 + T cell exhaustion undergone by those infected patients. During human CL, higher frequencies of CD4 + PD-1 + T cells were observed in active CL disease patients compared to post-treated patients and uninfected individuals ( 95 ). Interestingly, it was observed a continuously increasing frequency of PD-1 + T cells together with the development of CD4 + T cells subpopulations ( 95 ).…”

“…During human CL, higher frequencies of CD4 + PD-1 + T cells were observed in active CL disease patients compared to post-treated patients and uninfected individuals ( 95 ). Interestingly, it was observed a continuously increasing frequency of PD-1 + T cells together with the development of CD4 + T cells subpopulations ( 95 ). Lower frequencies of PD-1 + among T naïve (CD45RO - CCR7 + ) and higher frequencies among T terminally differentiated (CD45RO - CCR7 - ) ( 95 ).…”

“…Interestingly, it was observed a continuously increasing frequency of PD-1 + T cells together with the development of CD4 + T cells subpopulations ( 95 ). Lower frequencies of PD-1 + among T naïve (CD45RO - CCR7 + ) and higher frequencies among T terminally differentiated (CD45RO - CCR7 - ) ( 95 ).…”

“…Other studies have also previously described an upregulation of PD-1 and PD-L1 on T cells and macrophages, respectively, upon infection with L. infantum or L. donovani ( 85 , 102 ). Nevertheless, it was also demonstrated Pdl1 -/- mice infection with L. major induced lower frequencies of a population of CD4 + Ly6C hi effector T cells and higher frequencies of Foxp3 + Tregs compared with WT mice ( 95 ).…”

Total Glucosides of Paeony Ameliorate Pristane-Induced Lupus Nephritis by Inducing PD-1 ligands+ Macrophages via Activating IL-4/STAT6/PD-L2 Signaling

“…M2 macrophage is capable of inducing Tregs, suppressing the activation of T cells, phagocytosing apoptotic cells and inducing anti-inflammatory factors (8). Further, it has been reported that PD-1 ligands (PD-Ls) contribute to the M2 polarization and immunosuppressive effects of macrophages (9)(10)(11). In parallel with effects of PD-Ls on macrophages, adoptive transfer of PD-L2 + M2 macrophages delayed the progression of murine experimental autoimmune encephalomyelitis (EAE) (12).…”