Vaccination with Leishmania mexicana LPG induces PD-1 in CD8+ and PD-L2 in macrophages thereby suppressing the immune response: A model to assess vaccine efficacy

Martínez-Salazar, Berenice; Domínguez, J. Delgado; Estrada, Julio; Bonilla, C. Gonzalez; Becker, Ingeborg

doi:10.1016/j.vaccine.2014.01.016

Cited by 21 publications

(10 citation statements)

References 20 publications

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“…Another study corroborated these results using LPG ( Leishmania lipophosphaglycan) as a vaccine candidate against Leishmania infections ( 31 ). Vaccination with LPG did not protect mice from Leishmania mexicana infection, and LPG vaccination resulted in upregulation of PD-1 on CD8 + T cells.…”

Section: Coinhibitory Molecules Limit Recall Potentialmentioning

confidence: 63%

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

2018

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T cell co-signaling molecules play an important role in fine-tuning the strength of T cell activation during many types of immune responses, including infection, cancer, transplant rejection, and autoimmunity. Over the last few decades, intense research into these cosignaling molecules has provided rich evidence to suggest that cosignaling molecules may be harnessed for the treatment of immune-related diseases. In particular, coinhibitory molecules such as programmed-death 1, 2B4, BTLA, TIGIT, LAG-3, TIM-3, and CTLA-4 inhibit T cell responses by counteracting TCR and costimulatory signals, leading to the inhibition of proliferation and effector function and the downregulation of activation and adhesion molecules at the cell surface. While many reviews have focused on the role of coinhibitory molecules in modifying primary CD8+ T cell responses, in this review, we will consider the complex role of coinhibitory molecules in altering CD8+ T cell recall potential. As memory CD8+ T cell responses are critical for protective memory responses in infection and cancer and contribute to potentially pathogenic memory responses in transplant rejection and autoimmunity, understanding the role of coinhibitory receptor control of memory T cells may illuminate important aspects of therapeutically targeting these pathways.

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Section: Coinhibitory Molecules Limit Recall Potentialmentioning

confidence: 63%

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

2018

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“…major infection in BALB/c mice [ 68 ]. Martinez Salazar et al [ 71 ] suggested that L . mexicana LPG vaccination induced upregulation of programmed cell death protein 1 (PD-1), leading to functional CD8 + T cell inactivation and, consequently, disease progression.…”

Section: Discussionmentioning

confidence: 99%

An α-Gal-containing neoglycoprotein-based vaccine partially protects against murine cutaneous leishmaniasis caused by Leishmania major

et al. 2017

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BackgroundProtozoan parasites from the genus Leishmania cause broad clinical manifestations known as leishmaniases, which affect millions of people worldwide. Cutaneous leishmaniasis (CL), caused by L. major, is one the most common forms of the disease in the Old World. There is no preventive or therapeutic human vaccine available for L. major CL, and existing drug treatments are expensive, have toxic side effects, and resistant parasite strains have been reported. Hence, further therapeutic interventions against the disease are necessary. Terminal, non-reducing, and linear α-galactopyranosyl (α-Gal) epitopes are abundantly found on the plasma membrane glycolipids of L. major known as glycoinositolphospholipids. The absence of these α-Gal epitopes in human cells makes these glycans highly immunogenic and thus potential targets for vaccine development against CL.Methodology/Principal findingsHere, we evaluated three neoglycoproteins (NGPs), containing synthetic α-Gal epitopes covalently attached to bovine serum albumin (BSA), as vaccine candidates against L. major, using α1,3-galactosyltransferase-knockout (α1,3GalT-KO) mice. These transgenic mice, similarly to humans, do not express nonreducing, linear α-Gal epitopes in their cells and are, therefore, capable of producing high levels of anti-α-Gal antibodies. We observed that Galα(1,6)Galβ-BSA (NGP5B), but not Galα(1,4)Galβ-BSA (NGP12B) or Galα(1,3)Galα-BSA (NGP17B), was able to significantly reduce the size of footpad lesions by 96% in comparison to control groups. Furthermore, we observed a robust humoral and cellular immune response with production of high levels of protective lytic anti-α-Gal antibodies and induction of Th1 cytokines.Conclusions/SignificanceWe propose that NGP5B is an attractive candidate for the study of potential synthetic α-Gal-neoglycoprotein-based vaccines against L. major infection.

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“…To induce a strong cell-mediated immunity, e.g., after vaccination, adequate maturation of dendritic cells is important. In animal models, it was demonstrated that vaccination using L. mexicana LPG induced PD-1/PD-L2 expression on several immune cells in a dose dependent fashion ( 58 ). Blocking the PD-1/PD-L interaction could be a valuable approach to enhance efficacy of Leishmania vaccine candidates.…”

Section: Discussionmentioning

confidence: 99%

Nivolumab Enhances In Vitro Effector Functions of PD-1+ T-Lymphocytes and Leishmania-Infected Human Myeloid Cells in a Host Cell-Dependent Manner

et al. 2017

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Functional impairment of T-cells and a concomitant augmented expression of programmed death-1 (PD-1) have been observed in visceral leishmaniasis patients, as well as in experimental models for visceral and cutaneous leishmaniasis. The PD-1/PD-1-ligand (PD-1/PD-L) interaction negatively regulates T-cell effector functions, which are required for parasite control during leishmaniasis. The aim of this study was to elucidate the impact of the PD-1/PD-L axis in a human primary in vitro infection model of Leishmania major (Lm). Blocking the PD-1/PD-L interaction with nivolumab increased T-cell proliferation and release of the proinflammatory cytokines TNFα and IFNγ during the cocultivation of Lm-infected human monocyte-derived macrophages (hMDMs) or dendritic cells (hMDDC) with autologous PD-1+-lymphocytes. As a consequence Lm infection decreased, being the most pronounced in hMDDC, compared to proinflammatory hMDM1 and anti-inflammatory hMDM2. Focusing on hMDDC, we could partially reverse effects mediated by PD-1 blockade by neutralizing TNFα but not by neutralizing IFNγ. Furthermore, PD-1 blockade increased intracellular expression of perforin, granulysin, and granzymes in proliferating CD4+-T-cells, which might be implicated in reduction of Lm-infected cells. In all, our data describe an important role for the PD-1/PD-L axis upon Lm infection using a human primary cell system. These data contribute to a better understanding of the PD-1-induced T-cell impairment during disease and its influence on immune effector mechanisms to combat Lm infection.

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Vaccination with Leishmania mexicana LPG induces PD-1 in CD8+ and PD-L2 in macrophages thereby suppressing the immune response: A model to assess vaccine efficacy

Cited by 21 publications

References 20 publications

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

An α-Gal-containing neoglycoprotein-based vaccine partially protects against murine cutaneous leishmaniasis caused by Leishmania major

Nivolumab Enhances In Vitro Effector Functions of PD-1+ T-Lymphocytes and Leishmania-Infected Human Myeloid Cells in a Host Cell-Dependent Manner

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