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

TY - JOUR

T1 - Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4+ T Effector and Regulatory T Cells in Cutaneous Leishmaniasis

AU - Freitas e Silva, R.D.

AU - Gálvez, R.I.

AU - Pereira, V.R.A.

AU - de Brito, M.E.F.

AU - Choy, S.L.

AU - Lotter, H.

AU - Bosurgi, L.

AU - Jacobs, T.

PY - 2020

Y1 - 2020

N2 - 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 activatedCD4+ 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+Ly6Chi 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 byinfiltrating monocytes and lower levels of the Th1 cytokines IFN-g and TNF-a 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+Ly6Chi T effector cells and CD4+Foxp3+ regulatory T cells.

AB - 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 activatedCD4+ 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+Ly6Chi 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 byinfiltrating monocytes and lower levels of the Th1 cytokines IFN-g and TNF-a 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+Ly6Chi T effector cells and CD4+Foxp3+ regulatory T cells.

U2 - 10.3389/fimmu.2020.574491

DO - 10.3389/fimmu.2020.574491

M3 - SCORING: Journal article

C2 - 33193363

VL - 11

JO - FRONT IMMUNOL

JF - FRONT IMMUNOL

SN - 1664-3224

M1 - 574491

ER -