Jaime Fuentealba - Academia.edu (original) (raw)

Papers by Jaime Fuentealba

bioRxiv (Cold Spring Harbor Laboratory), May 15, 2024

Ac@va@on of CD8+ T cells leads to the differen@a@on of short-lived terminal effectors and memory ... more Ac@va@on of CD8+ T cells leads to the differen@a@on of short-lived terminal effectors and memory precursors. Some of these memory precursors remain in lymphoid organs and become long-lived central memory T cells (TCM), while others home to non-lymphoid peripheral @ssues early aQer an@gen recogni@on and differen@ate into @ssue resident memory T cells (TRM). The early stages of memory precursor @ssue homing and TRM differen@a@on remain poorly understood. We show here that at steady state, during spaceinduced "homeosta@c" expansion, and aQer flu infec@on, dele@on of the histone 3-lysine 9 methyltransferase SUV39H1 in CD8 + T cells, increases the homing to non-lymphoid @ssues (including liver, lungs, gut and skin). SUV39H1-defec@ve cells in @ssues express CD49d and differen@ate into CD69+/CD103-TRM aQer adop@ve transfer or Flu infec@on. SUV39H1defec@ve T cells that accumulate in lungs are fully func@onal in both Flu re-infec@on and lung tumor models. We conclude that SUV39H1 restrains CD8 + T cell @ssue homing and TRM differen@a@on in WT mice. These results should encourage the use of SUV39H1-deple@on in the context of adop@ve T cell therapies to enhance @ssue homing, thereby op@mizing the efficiency of target cell eradica@on and long-term protec@on in the context of infec@on and cancer.

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the ... more Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) associated to the aggregation of α-synuclein (α-Syn) that forms intraneuronal inclusions. In addition, mounting evidence suggest that neuro-immune interactions, favoured by cerebrovascular alterations, are involved in the pathomechanisms of PD. In this work, we focus on a myeloid population that surrounds blood vessels: perivascular macrophages (PVMs). We show that both in PD patients and in a mouse model of degenerative synucleinopathy, there is an increased proliferative recruitment of PVMs within the SN. We also found that specific ablation of PVMs aggravates the degenerative phenotype in synucleinopathic mice. PVMs-mediated neuroprotection is not likely linked to regulatory mechanisms of microglial cell response. Interestingly, the absence of PVMs is associated with higher vascular expression of VCAM-1 and enhanced infiltration of CD4+ and CD8+ T-cells, whose pa...

Science Immunology, 2021

Inactivation of SOCS1 optimizes adoptive T cell therapy including human CAR-T cell composition an... more Inactivation of SOCS1 optimizes adoptive T cell therapy including human CAR-T cell composition and efficacy.

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the ... more Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) associated to the aggregation of α-synuclein (α-Syn) that forms intraneuronal inclusions. In addition, mounting evidence suggest that neuro-immune interactions, favoured by cerebrovascular alterations, are involved in the pathomechanisms of PD. In this work, we focus on a myeloid population that surrounds blood vessels: perivascular macrophages (PVMs). We show that both in PD patients and in a mouse model of degenerative synucleinopathy, there is an increased proliferative recruitment of PVMs within the SN. We also found that specific ablation of PVMs aggravates the degenerative phenotype in synucleinopathic mice. PVMs-mediated neuroprotection is not likely linked to regulatory mechanisms of microglial cell response. Interestingly, the absence of PVMs is associated with higher vascular expression of VCAM-1 and enhanced infiltration of CD4+ and CD8+ T-cells, whose pa...

Cancers, 2021

Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBC... more Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell (non-GCB) origin. It is associated with a poor prognosis and an unmet medical need. Immunotherapy has emerged as one of the most promising areas of research and is now part of the standard treatment for many solid and hematologic tumors. This new class of therapy generated great enthusiasm for the treatment of relapsed/refractory PCNSL. Here, we discuss the challenges of immunotherapy for PCNSL represented by the lymphoma cell itself and the specific immune brain microenvironment. We review the current clinical development from the anti-CD20 monoclonal antibody to CAR-T cells, as well as immune checkpoint inhibitors and targeted therapies with off-tumor effects on the brain microenvironment. Perspectives for improving the efficacy of immunotherapies and optimizing their therapeutic role in PCNSL are suggested.

Gene Expression Patterns, 2016

Heterotrimeric G protein signaling plays major roles during different cellular events. However, t... more Heterotrimeric G protein signaling plays major roles during different cellular events. However, there is a limited understanding of the molecular mechanisms underlying G protein control during embryogenesis. G proteins are highly conserved and can be grouped into four subfamilies according to sequence homology and function. To further studies on G protein function during embryogenesis, the present analysis identified four Ga subunits representative of the different subfamilies and determined their spatiotemporal expression patterns during Xenopus tropicalis embryogenesis. Each of the Ga subunit transcripts was maternally and zygotically expressed, and, as development progressed, dynamic expression patterns were observed. In the early developmental stages, the Ga subunits were expressed in the animal hemisphere and dorsal marginal zone. While expression was observed at the somite boundaries, in vascular structures, in the eye, and in the otic vesicle during the later stages, expression was mainly found in neural tissues, such as the neural tube and, especially, in the cephalic vesicles, neural crest region, and neural crest-derived structures. Together, these results support the pleiotropism and complexity of G protein subfamily functions in different cellular events. The present study constitutes the most comprehensive description to date of the spatiotemporal expression patterns of Ga subunits during vertebrate development.

Proceedings of the Royal Society B: Biological Sciences, 2013

The vertebrates share the ability to produce a skeleton made of mineralized extracellular matrix.... more The vertebrates share the ability to produce a skeleton made of mineralized extracellular matrix. However, our understanding of the molecular changes that accompanied their emergence remains scarce. Here, we describe the evolutionary history of the SPARC (secreted protein acidic and rich in cysteine) family, because its vertebrate orthologues are expressed in cartilage, bones and teeth where they have been proposed to bind calcium and act as extracellular collagen chaperones, and because further duplications of specific SPARC members produced the small calcium-binding phosphoproteins (SCPP) family that is crucial for skeletal mineralization to occur. Both phylogeny and synteny conservation analyses reveal that, in the eumetazoan ancestor, a unique ancestral gene duplicated to give rise toSPARCandSPARCBdescribed here for the first time. Independent losses have eliminated one of the two paralogues in cnidarians, protostomes and tetrapods. Hence, only non-tetrapod deuterostomes have co...

Gene Expression Patterns, 2011

RIC-8 is a highly conserved protein that promotes G protein signaling as it acts as a Guanine nuc... more RIC-8 is a highly conserved protein that promotes G protein signaling as it acts as a Guanine nucleotide Exchanging Factor (GEF) over a subset of Ga subunits. In invertebrates, RIC-8 plays crucial roles in synaptic transmission as well as in asymmetric cell division. As a first step to address further studies on RIC-8 function in vertebrates, here we have cloned a ric-8 gene from Xenopus tropicalis (xtric-8) and determined its spatiotemporal expression pattern throughout embryogenesis. The xtric-8 transcript is expressed maternally and zygotically and, as development proceeds, it shows a dynamic expression pattern. At early developmental stages, xtric-8 is expressed in the animal hemisphere, whereas its expression is later restricted to neural tissues, such as the neural tube and the brain, as well as in the eye and neural crestderived structures, including those of the craniofacial region. Together, our findings suggest that RIC-8 functions are related to the development of the nervous system.

Developmental Biology, 2011

Developmental Biology, 2011

Developmental Biology, 2013

The cerebellum consists of an intricate array of lobules that arises during the process of foliat... more The cerebellum consists of an intricate array of lobules that arises during the process of foliation. Foliation not only increases surface area, but may also facilitate organization of cerebellar neural circuitry. Defects in cerebellar foliation are associated with a number of diseases. Yet, little is known about how foliation, a process involving large-scale and simultaneous movement of several different cell types, is coordinated by cell-cell signaling at the molecular level. Here we show that Ric-8a, a guanine nucleotide exchange factor in the G-proteincoupled receptor pathway, is specifically required in Bergmann glia during cerebellar foliation. We find that ric-8a mutation in mice results in disorganized Bergmann glial scaffolding, defective granule cell migration, and disrupted Purkinje cell positioning. These abnormalities result from primary defects in Bergmann glia since mutations in granule cells do not show similar effects. They first arise during late embryogenesis, at the onset of foliation, when ric-8a mutant Bergmann glia fail to maintain adhesion to the basement membrane specifically at emerging fissures. This suggests that Ric-8a is essential for the enhanced Bergmann glia-basement membrane adhesion required for fissure formation. Indeed, we find that ric-8a-deficient cerebellar glia show decreased affinity for basement membrane components. We also find that weakening Bergmann glia-basement membrane interaction by ␤1 integrin deletion results in a similar phenotype. These results thus reveal a novel role of Ric-8a in modulating Bergmann glia-basement membrane adhesion during foliation, and provide new insights into the signaling pathways that coordinate cellular movement during cerebellar morphogenesis.

SummaryThe expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using i... more SummaryThe expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using in vivo genome-wide CRISPR-Cas9 screens, we identified SOCS1 as a non-redundant checkpoint imposing a brake on CD4+ T-cell proliferation upon rechallenge. We show here that SOCS1 is a critical node integrating both IL-2 and IFN-γ signals and blocking multiple signaling pathways to abrogate CD4+ Th1 cell response. In CD8+ T-cell, SOCS1 does not impact the proliferation but rather reduces survival and effector functions. By targeting SOCS1, both murine and human CD4+ T-cell antitumor adoptive therapies exhibit a restored intra-tumor accumulation, proliferation/survival, persistence and polyfunctionality, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of primed CD4+ T cells, opening new possibilities to optimize CAR-T cell therapies composition and efficacy.

Developmental Biology, 2013

The neural crest (NC) is a transient embryonic structure induced at the border of the neural plat... more The neural crest (NC) is a transient embryonic structure induced at the border of the neural plate. NC cells extensively migrate towards diverse regions of the embryo, where they differentiate into various derivatives, including most of the craniofacial skeleton and the peripheral nervous system. The Ric-8A protein acts as a guanine nucleotide exchange factor for several Gα subunits, and thus behaves as an activator of signaling pathways mediated by heterotrimeric G proteins. Using in vivo transplantation assays, we demonstrate that Ric-8A levels are critical for the migration of cranial NC cells and their subsequent differentiation into craniofacial cartilage during Xenopus development. NC cells explanted from Ric-8A morphant embryos are unable to migrate directionally towards a source of the Sdf1 peptide, a potent chemoattractant for NC cells. Consistently, Ric-8A knock-down showed anomalous radial migratory behavior, displaying a strong reduction in cell spreading and focal adhesion formation. We further show that during in vivo and in vitro neural crest migration, Ric-8A localizes to the cell membrane, in agreement with its role as a G protein activator. We propose that Ric-8A plays essential roles during the migration of cranial NC cells, possibly by regulating cell adhesion and spreading.

bioRxiv (Cold Spring Harbor Laboratory), May 15, 2024

Ac@va@on of CD8+ T cells leads to the differen@a@on of short-lived terminal effectors and memory ... more Ac@va@on of CD8+ T cells leads to the differen@a@on of short-lived terminal effectors and memory precursors. Some of these memory precursors remain in lymphoid organs and become long-lived central memory T cells (TCM), while others home to non-lymphoid peripheral @ssues early aQer an@gen recogni@on and differen@ate into @ssue resident memory T cells (TRM). The early stages of memory precursor @ssue homing and TRM differen@a@on remain poorly understood. We show here that at steady state, during spaceinduced "homeosta@c" expansion, and aQer flu infec@on, dele@on of the histone 3-lysine 9 methyltransferase SUV39H1 in CD8 + T cells, increases the homing to non-lymphoid @ssues (including liver, lungs, gut and skin). SUV39H1-defec@ve cells in @ssues express CD49d and differen@ate into CD69+/CD103-TRM aQer adop@ve transfer or Flu infec@on. SUV39H1defec@ve T cells that accumulate in lungs are fully func@onal in both Flu re-infec@on and lung tumor models. We conclude that SUV39H1 restrains CD8 + T cell @ssue homing and TRM differen@a@on in WT mice. These results should encourage the use of SUV39H1-deple@on in the context of adop@ve T cell therapies to enhance @ssue homing, thereby op@mizing the efficiency of target cell eradica@on and long-term protec@on in the context of infec@on and cancer.

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the ... more Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) associated to the aggregation of α-synuclein (α-Syn) that forms intraneuronal inclusions. In addition, mounting evidence suggest that neuro-immune interactions, favoured by cerebrovascular alterations, are involved in the pathomechanisms of PD. In this work, we focus on a myeloid population that surrounds blood vessels: perivascular macrophages (PVMs). We show that both in PD patients and in a mouse model of degenerative synucleinopathy, there is an increased proliferative recruitment of PVMs within the SN. We also found that specific ablation of PVMs aggravates the degenerative phenotype in synucleinopathic mice. PVMs-mediated neuroprotection is not likely linked to regulatory mechanisms of microglial cell response. Interestingly, the absence of PVMs is associated with higher vascular expression of VCAM-1 and enhanced infiltration of CD4+ and CD8+ T-cells, whose pa...

Science Immunology, 2021

Inactivation of SOCS1 optimizes adoptive T cell therapy including human CAR-T cell composition an... more Inactivation of SOCS1 optimizes adoptive T cell therapy including human CAR-T cell composition and efficacy.

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the ... more Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) associated to the aggregation of α-synuclein (α-Syn) that forms intraneuronal inclusions. In addition, mounting evidence suggest that neuro-immune interactions, favoured by cerebrovascular alterations, are involved in the pathomechanisms of PD. In this work, we focus on a myeloid population that surrounds blood vessels: perivascular macrophages (PVMs). We show that both in PD patients and in a mouse model of degenerative synucleinopathy, there is an increased proliferative recruitment of PVMs within the SN. We also found that specific ablation of PVMs aggravates the degenerative phenotype in synucleinopathic mice. PVMs-mediated neuroprotection is not likely linked to regulatory mechanisms of microglial cell response. Interestingly, the absence of PVMs is associated with higher vascular expression of VCAM-1 and enhanced infiltration of CD4+ and CD8+ T-cells, whose pa...

Cancers, 2021

Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBC... more Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell (non-GCB) origin. It is associated with a poor prognosis and an unmet medical need. Immunotherapy has emerged as one of the most promising areas of research and is now part of the standard treatment for many solid and hematologic tumors. This new class of therapy generated great enthusiasm for the treatment of relapsed/refractory PCNSL. Here, we discuss the challenges of immunotherapy for PCNSL represented by the lymphoma cell itself and the specific immune brain microenvironment. We review the current clinical development from the anti-CD20 monoclonal antibody to CAR-T cells, as well as immune checkpoint inhibitors and targeted therapies with off-tumor effects on the brain microenvironment. Perspectives for improving the efficacy of immunotherapies and optimizing their therapeutic role in PCNSL are suggested.

Gene Expression Patterns, 2016

Heterotrimeric G protein signaling plays major roles during different cellular events. However, t... more Heterotrimeric G protein signaling plays major roles during different cellular events. However, there is a limited understanding of the molecular mechanisms underlying G protein control during embryogenesis. G proteins are highly conserved and can be grouped into four subfamilies according to sequence homology and function. To further studies on G protein function during embryogenesis, the present analysis identified four Ga subunits representative of the different subfamilies and determined their spatiotemporal expression patterns during Xenopus tropicalis embryogenesis. Each of the Ga subunit transcripts was maternally and zygotically expressed, and, as development progressed, dynamic expression patterns were observed. In the early developmental stages, the Ga subunits were expressed in the animal hemisphere and dorsal marginal zone. While expression was observed at the somite boundaries, in vascular structures, in the eye, and in the otic vesicle during the later stages, expression was mainly found in neural tissues, such as the neural tube and, especially, in the cephalic vesicles, neural crest region, and neural crest-derived structures. Together, these results support the pleiotropism and complexity of G protein subfamily functions in different cellular events. The present study constitutes the most comprehensive description to date of the spatiotemporal expression patterns of Ga subunits during vertebrate development.

Proceedings of the Royal Society B: Biological Sciences, 2013

The vertebrates share the ability to produce a skeleton made of mineralized extracellular matrix.... more The vertebrates share the ability to produce a skeleton made of mineralized extracellular matrix. However, our understanding of the molecular changes that accompanied their emergence remains scarce. Here, we describe the evolutionary history of the SPARC (secreted protein acidic and rich in cysteine) family, because its vertebrate orthologues are expressed in cartilage, bones and teeth where they have been proposed to bind calcium and act as extracellular collagen chaperones, and because further duplications of specific SPARC members produced the small calcium-binding phosphoproteins (SCPP) family that is crucial for skeletal mineralization to occur. Both phylogeny and synteny conservation analyses reveal that, in the eumetazoan ancestor, a unique ancestral gene duplicated to give rise toSPARCandSPARCBdescribed here for the first time. Independent losses have eliminated one of the two paralogues in cnidarians, protostomes and tetrapods. Hence, only non-tetrapod deuterostomes have co...

Gene Expression Patterns, 2011

RIC-8 is a highly conserved protein that promotes G protein signaling as it acts as a Guanine nuc... more RIC-8 is a highly conserved protein that promotes G protein signaling as it acts as a Guanine nucleotide Exchanging Factor (GEF) over a subset of Ga subunits. In invertebrates, RIC-8 plays crucial roles in synaptic transmission as well as in asymmetric cell division. As a first step to address further studies on RIC-8 function in vertebrates, here we have cloned a ric-8 gene from Xenopus tropicalis (xtric-8) and determined its spatiotemporal expression pattern throughout embryogenesis. The xtric-8 transcript is expressed maternally and zygotically and, as development proceeds, it shows a dynamic expression pattern. At early developmental stages, xtric-8 is expressed in the animal hemisphere, whereas its expression is later restricted to neural tissues, such as the neural tube and the brain, as well as in the eye and neural crestderived structures, including those of the craniofacial region. Together, our findings suggest that RIC-8 functions are related to the development of the nervous system.

Developmental Biology, 2011

Developmental Biology, 2011

Developmental Biology, 2013

The cerebellum consists of an intricate array of lobules that arises during the process of foliat... more The cerebellum consists of an intricate array of lobules that arises during the process of foliation. Foliation not only increases surface area, but may also facilitate organization of cerebellar neural circuitry. Defects in cerebellar foliation are associated with a number of diseases. Yet, little is known about how foliation, a process involving large-scale and simultaneous movement of several different cell types, is coordinated by cell-cell signaling at the molecular level. Here we show that Ric-8a, a guanine nucleotide exchange factor in the G-proteincoupled receptor pathway, is specifically required in Bergmann glia during cerebellar foliation. We find that ric-8a mutation in mice results in disorganized Bergmann glial scaffolding, defective granule cell migration, and disrupted Purkinje cell positioning. These abnormalities result from primary defects in Bergmann glia since mutations in granule cells do not show similar effects. They first arise during late embryogenesis, at the onset of foliation, when ric-8a mutant Bergmann glia fail to maintain adhesion to the basement membrane specifically at emerging fissures. This suggests that Ric-8a is essential for the enhanced Bergmann glia-basement membrane adhesion required for fissure formation. Indeed, we find that ric-8a-deficient cerebellar glia show decreased affinity for basement membrane components. We also find that weakening Bergmann glia-basement membrane interaction by ␤1 integrin deletion results in a similar phenotype. These results thus reveal a novel role of Ric-8a in modulating Bergmann glia-basement membrane adhesion during foliation, and provide new insights into the signaling pathways that coordinate cellular movement during cerebellar morphogenesis.

SummaryThe expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using i... more SummaryThe expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using in vivo genome-wide CRISPR-Cas9 screens, we identified SOCS1 as a non-redundant checkpoint imposing a brake on CD4+ T-cell proliferation upon rechallenge. We show here that SOCS1 is a critical node integrating both IL-2 and IFN-γ signals and blocking multiple signaling pathways to abrogate CD4+ Th1 cell response. In CD8+ T-cell, SOCS1 does not impact the proliferation but rather reduces survival and effector functions. By targeting SOCS1, both murine and human CD4+ T-cell antitumor adoptive therapies exhibit a restored intra-tumor accumulation, proliferation/survival, persistence and polyfunctionality, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of primed CD4+ T cells, opening new possibilities to optimize CAR-T cell therapies composition and efficacy.

Developmental Biology, 2013

The neural crest (NC) is a transient embryonic structure induced at the border of the neural plat... more The neural crest (NC) is a transient embryonic structure induced at the border of the neural plate. NC cells extensively migrate towards diverse regions of the embryo, where they differentiate into various derivatives, including most of the craniofacial skeleton and the peripheral nervous system. The Ric-8A protein acts as a guanine nucleotide exchange factor for several Gα subunits, and thus behaves as an activator of signaling pathways mediated by heterotrimeric G proteins. Using in vivo transplantation assays, we demonstrate that Ric-8A levels are critical for the migration of cranial NC cells and their subsequent differentiation into craniofacial cartilage during Xenopus development. NC cells explanted from Ric-8A morphant embryos are unable to migrate directionally towards a source of the Sdf1 peptide, a potent chemoattractant for NC cells. Consistently, Ric-8A knock-down showed anomalous radial migratory behavior, displaying a strong reduction in cell spreading and focal adhesion formation. We further show that during in vivo and in vitro neural crest migration, Ric-8A localizes to the cell membrane, in agreement with its role as a G protein activator. We propose that Ric-8A plays essential roles during the migration of cranial NC cells, possibly by regulating cell adhesion and spreading.