Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases

Ibañez-Vega, Jorge; Vilchez, Constanza; Jimenez, Karin; Guevara, Carlos; Burgos, Paula I.; Naves, Rodrigo

doi:10.1016/j.jaut.2021.102702

Cited by 24 publications

(24 citation statements)

References 159 publications

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“…PD-1 is a monomeric transmembrane glycoprotein that shares homology with the B7/CD28 family of T cell signaling molecules [ 19 , 20 ]. PD-1 interacts with its ligands PD-L1 and/or PD-L2 to provide a negative regulatory signal to CD4+ and CD8+ T cells that results ultimately in a phenotype termed T cell exhaustion [ 21 ]. This may be an important pathogenic factor in RRMS, given that PD-1 is a strong inhibitor of T cell activity.…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of PD-1 in Circulating CD4+ and CD8+ Tregs Is an Early Feature of RRMS

Machcińska

Kierasińska

Michniowska

et al. 2022

IJMS

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Altered regulatory T cell (Treg) function could contribute to MS. The expression of activating and inhibitory receptors influences the activity of Tregs. Our aim was to investigate T cell phenotypes in relapsing–remitting MS (RRMS) patients at an early phase of the disease. We examined the influence of demographic parameters on the distribution of CD4+ and CD8+ T cell subclasses by generalized linear modeling. We also studied the expression of the following markers—CTLA-4, GITR, PD-1, FoxP3, Helios, CD28, CD62L, CD103—on T cell subsets from peripheral blood with a 14-color flow cytometry panel. We used an antibody array to define the profiles of 34 Th1/Th2/Th17 cytokines in the serum. Expression of PD-1 and GITR on CD4+ and CD8+ Tregs was decreased in RRMS patients. The proinflammatory factors IFN-γ, IL-17, IL-17F, TGFβ-1, TGFβ-3, IL-1SRII, IL-12 p40, sgp130, IL-6sR were significantly increased in RRMS patients. Therefore, a deficiency of PD-1 and GITR immune checkpoints on CD4+ and CD8+ Tregs is a feature of RRMS and might underlie impaired T cell control.

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Section: Discussionmentioning

confidence: 99%

Reduced Expression of PD-1 in Circulating CD4+ and CD8+ Tregs Is an Early Feature of RRMS

Machcińska

Kierasińska

Michniowska

et al. 2022

IJMS

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show abstract

“…Similar to CTLA-4, the PD-L1/PD-1 axis also plays a pivotal role in inducing peripheral tolerance. However, the latter is distinct because it can be simultaneously expressed on the surface of DCs and Tregs ( 63 , 64 ). Generally, cells with expression of PD-L1 play a regulatory role.…”

Section: Bidirectional Dc-treg Cell Crosstalk In Ms Patients and Eae ...mentioning

confidence: 99%

“…A previous study in EAE has shown that steady-state DCs exhibited their suppressive capacity by promoting the development of Tregs, thereby improving CNS autoimmunity ( 6 ). Further research has demonstrated that the generation of DC-dependent Tregs was guided by the interaction between PD-L1 on DCs and PD-1 expressed by T Cells ( 6 , 64 ). Paradoxically, one study showed that PD-L1 expressed on DCs was important for the inhibition of follicular regulatory T (Tfr) cell differentiation and maintenance ( 71 ).…”

Section: Bidirectional Dc-treg Cell Crosstalk In Ms Patients and Eae ...mentioning

confidence: 99%

Crosstalk between dendritic cells and regulatory T cells: Protective effect and therapeutic potential in multiple sclerosis

Yang

et al. 2022

Front. Immunol.

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system related to autoimmunity and is characterized by demyelination, neuroinflammation, and neurodegeneration. Cell therapies mediated by dendritic cells (DCs) and regulatory T cells (Tregs) have gradually become accumulating focusing in MS, and the protective crosstalk mechanisms between DCs and Tregs provide the basis for the efficacy of treatment regimens. In MS and its animal model experimental autoimmune encephalomyelitis, DCs communicate with Tregs to form immune synapses and complete a variety of complex interactions to counteract the unbalanced immune tolerance. Through different co-stimulatory/inhibitory molecules, cytokines, and metabolic enzymes, DCs regulate the proliferation, differentiation and function of Tregs. On the other hand, Tregs inhibit the mature state and antigen presentation ability of DCs, ultimately improving immune tolerance. In this review, we summarized the pivotal immune targets in the interaction between DCs and Tregs, and elucidated the protective mechanisms of DC-Treg cell crosstalk in MS, finally interpreted the complex cell interplay in the manner of inhibitory feedback loops to explore novel therapeutic directions for MS.

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“…After translation, post-translational modifications such as fucosylation and N-glycosylation are crucial for PD-1 stability, and PD-1 stability can also be affected by miRNA. Once the stability of PD-1 is broken, it is degraded by proteasome and lysosome [ 56 ]. PD-1 has been localized in vesicles near the Golgi and TGN.…”

Section: Checkpoint Trafficking Mediated By Endosomal-lysosomal Systemmentioning

confidence: 99%

“…These PD-1 vesicle reservoirs are waiting for TCR activation. Once PD-1 vesicles reach the plasma membrane, it can be ubiquitylated, triggering endocytosis and degradation [ 56 ]. Like PD-L1, the palmitoylation of PD-1 promotes the interaction between PD-1 and Rab11, promoting PD-1 transport to the recycling endosome and attenuating the degradation in the lysosome.…”

Section: Checkpoint Trafficking Mediated By Endosomal-lysosomal Systemmentioning

confidence: 99%

Membrane protein trafficking in the anti-tumor immune response: work of endosomal-lysosomal system

2022

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Immunotherapy has changed the treatment landscape for multiple cancer types. In the recent decade, great progress has been made in immunotherapy, including immune checkpoint inhibitors, adoptive T-cell therapy, and cancer vaccines. ICIs work by reversing tumor-induced immunosuppression, resulting in robust activation of the immune system and lasting immune responses. Whereas, their clinical use faces several challenges, especially the low response rate in most patients. As an increasing number of studies have focused on membrane immune checkpoint protein trafficking and degradation, which interferes with response to immunotherapy, it is necessary to summarize the mechanism regulating those transmembrane domain proteins translocated into the cytoplasm and degraded via lysosome. In addition, other immune-related transmembrane domain proteins such as T-cell receptor and major histocompatibility are associated with neoantigen presentation. The endosomal-lysosomal system can also regulate TCR and neoantigen-MHC complexes on the membrane to affect the efficacy of adoptive T-cell therapy and cancer vaccines. In conclusion, we discuss the process of surface delivery, internalization, recycling, and degradation of immune checkpoint proteins, TCR, and neoantigen-MHC complexes on the endosomal-lysosomal system in biology for optimizing cancer immunotherapy.

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Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases

Cited by 24 publications

References 159 publications

Reduced Expression of PD-1 in Circulating CD4+ and CD8+ Tregs Is an Early Feature of RRMS

Reduced Expression of PD-1 in Circulating CD4+ and CD8+ Tregs Is an Early Feature of RRMS

Crosstalk between dendritic cells and regulatory T cells: Protective effect and therapeutic potential in multiple sclerosis

Membrane protein trafficking in the anti-tumor immune response: work of endosomal-lysosomal system

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