Immune Checkpoint Inhibition-related Neuroinflammation Disrupts Cognitive Function.

Combinatorial blockade of Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improve the progression-free survival of individuals with metastatic cancers, including melanoma. In addition to unleashing anti-tumor immunity, combination immune checkpoint inhibition (ICI) disrupts immune-regulatory networks critical for maintaining homeostasis in various tissues, including the central nervous system (CNS). Although ICI- and cancer-related cognitive impairments (CRCI) in survivors are increasingly becoming evident, our understanding of ICI-induced immune-related adverse effects (IREA) in the CNS remains incomplete. Here, our murine melanoma model reveals that combination ICI impairs hippocampal-dependent learning and memory, as well as memory consolidation processes. Mechanistically, combination ICI disrupted synaptic integrity, and neuronal plasticity, reduced myelin, and further predisposed CNS for exaggerated experimental autoimmune encephalomyelitis. Combination ICI substantially altered both lymphoid and myeloid cells in the CNS. Neurogenesis was unaffected, however, microglial activation persisted for two-months post- ICI, concurrently with cognitive deficits, which parallels clinical observations in survivors. Overall, our results demonstrate that blockade of CTLA-4 and PD-1 alters neuro-immune homeostasis and activates microglia, promoting long-term neurodegeneration and driving cognitive impairments. Therefore, limiting microglial activation is a potential avenue to mitigate CNS IRAE while maintaining the therapeutic benefits of rapidly evolving ICIs and their combinations. SIGNIFICANCE: Despite the superior therapeutic efficacy of immune checkpoint inhibition (ICI) for cancers, its undesired effects on brain function are not fully understood. Here, we demonstrate that combination ICI elevates neuroinflammation, activates microglia, leading to detrimental neurodegenerative and neurocognitive sequelae.

Piezo1 channels restrain regulatory T cells but are dispensable for effector CD4+ T cell responses.

T lymphocytes encounter complex mechanical cues during an immune response. The mechanosensitive ion channel, Piezo1, drives inflammatory responses to bacterial infections, wound healing, and cancer; however, its role in helper T cell function remains unclear. In an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we found that mice with genetic deletion of Piezo1 in T cells showed diminished disease severity. Unexpectedly, Piezo1 was not essential for lymph node homing, interstitial motility, Ca2+ signaling, T cell proliferation, or differentiation into proinflammatory T helper 1 (TH1) and TH17 subsets. However, Piezo1 deletion in T cells resulted in enhanced transforming growth factor-ß (TGFß) signaling and an expanded pool of regulatory T (Treg) cells. Moreover, mice with deletion of Piezo1 specifically in Treg cells showed significant attenuation of EAE. Our results indicate that Piezo1 selectively restrains Treg cells, without influencing activation events or effector T cell functions.

Regulatory T cells suppress Th17 cell Ca2+ signaling in the spinal cord during murine autoimmune neuroinflammation.

T lymphocyte motility and interaction dynamics with other immune cells are vital determinants of immune responses. Regulatory T (Treg) cells prevent autoimmune disorders by suppressing excessive lymphocyte activity, but how interstitial motility patterns of Treg cells limit neuroinflammation is not well understood. We used two-photon microscopy to elucidate the spatial organization, motility characteristics, and interactions of endogenous Treg and Th17 cells together with antigen-presenting cells (APCs) within the spinal cord leptomeninges in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Th17 cells arrive before the onset of clinical symptoms, distribute uniformly during the peak, and decline in numbers during later stages of EAE. In contrast, Treg cells arrive after Th17 cells and persist during the chronic phase. Th17 cells meander widely, interact with APCs, and exhibit cytosolic Ca2+ transients and elevated basal Ca2+ levels before the arrival of Treg cells. In contrast, Treg cells adopt a confined, repetitive-scanning motility while contacting APCs. These locally confined but highly motile Treg cells limit Th17 cells from accessing APCs and suppress Th17 cell Ca2+ signaling by a mechanism that is upstream of store-operated Ca2+ entry. Finally, Treg cell depletion increases APC numbers in the spinal cord and exaggerates ongoing neuroinflammation. Our results point to fundamental differences in motility characteristics between Th17 and Treg cells in the inflamed spinal cord and reveal three potential cellular mechanisms by which Treg cells regulate Th17 cell effector functions: reduction of APC density, limiting access of Th17 cells to APCs, and suppression of Th17 Ca2+ signaling.

T-cell calcium dynamics visualized in a ratiometric tdTomato-GCaMP6f transgenic reporter mouse.

Calcium is an essential cellular messenger that regulates numerous functions in living organisms. Here, we describe development and characterization of 'Salsa6f', a fusion of GCaMP6f and tdTomato optimized for cell tracking while monitoring cytosolic Ca2+, and a transgenic Ca2+ reporter mouse with Salsa6f targeted to the Rosa26 locus for Cre-dependent expression in specific cell types. The development and function of T cells was unaffected in Cd4-Salsa6f mice. We describe Ca2+ signals reported by Salsa6f during T cell receptor activation in naive T cells, helper Th17 T cells and regulatory T cells, and Ca2+ signals mediated in T cells by an activator of mechanosensitive Piezo1 channels. Transgenic expression of Salsa6f enables ratiometric imaging of Ca2+ signals in complex tissue environments found in vivo. Two-photon imaging of migrating T cells in the steady-state lymph node revealed both cell-wide and localized sub-cellular Ca2+ transients ('sparkles') as cells migrate.

Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.

We have recently described sustained clinical recovery associated with dampened neuroinflammation and remyelination following transplantation of neural precursor cells (NPCs) derived from human embryonic stem cells (hESCs) in a viral model of the human demyelinating disease multiple sclerosis. The hNPCs used in that study were derived by a novel direct differentiation method (direct differentiation, DD-NPCs) that resulted in a unique gene expression pattern when compared to hNPCs derived by conventional methods. Since the therapeutic potential of human NPCs may differ greatly depending on the method of derivation and culture, we wanted to determine whether NPCs differentiated using conventional methods would be similarly effective in improving clinical outcome under neuroinflammatory demyelinating conditions. For the current study, we utilized hNPCs differentiated from a human induced pluripotent cell line via an embryoid body intermediate stage (EB-NPCs). Intraspinal transplantation of EB-NPCs into mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in decreased accumulation of CD4+ T cells in the central nervous system that was concomitant with reduced demyelination at the site of injection. Dampened neuroinflammation and remyelination was correlated with a transient increase in CD4+FOXP3+ regulatory T cells (Tregs) concentrated within the peripheral lymphatics. However, compared to our earlier study, pathological improvements were modest and did not result in significant clinical recovery. We conclude that the genetic signature of NPCs is critical to their effectiveness in this model of viral-induced neurologic disease. These comparisons will be useful for understanding what factors are critical for the sustained clinical improvement.

Capacidad antioxidante total en alimentos convencionales y regionales de Chiapas, México / Total antioxidant capability of conventional and regional foods in Chiapas, Mexico

OBJETVIO: evaluar la capacidad antioxidante total de 24 alimentos convencionales y nueve propios de la región del Estado de Chiapas. MÉTODOS: los alimentos fueron recolectados en el Mercado "Rafael Pascacio Gamboa" de Tuxtla Gutiérrez:17 pertenecientes al grupo de vegetales o verduras, siete al grupo de frutas y nueve considerados regionales. Para determinar la capacidad antioxidante total se empleó la técnica de Miller y otros que se basa en la formación de un radical de coloración verde azulada que se mide a 600 nm. Esta coloración es proporcional a la actividad antioxidante y se mide por comparación con un patrón que es un derivado sintético de la vitamina E. RESULTADOS: los mayores valores de capacidad antioxidante se encontró en la calabacita cocida y los menores en el pepino; otros vegetales como el aguacate, berro, lechuga y cebolla, tenían valores superiores a los encontrados en estas especies cultivadas en Cuba. En las frutas, sucedió al revés, correspondieron los mayores valores a la guayaba, naranja y papaya cultivada en Cuba. Los alimentos regionales mejores por su capacidad antioxidante resultaron ser la verdolaga y la yerba buena. CONCLUSIONES: con los resultados alcanzados se espera contribuir a diseminar la importancia de ingerir aquellos alimentos que por su capacidad antioxidante protegen al organismo de la acción de los radicales libres, causantes de los procesos de envejecimiento y de algunas enfermedades.

OBJECTIVES: To evaluate the total antioxidant capability of 24 conventional foods and nine regional foods from Chiapas state. METHODS: The foods were picked up at "Rafael Pascacio Gamboa" marketplace of Tuxtla Gutiérrez: 17 foods from the vegetable or greenery group, seven from the fruit group and nine that were considered regional. To determine the total antioxidant capability, we used Miller et al's technique that is based on the formation of a green-blue coloured radical measured at 600nm. This colouring is proportional to antioxidant activity and is measured by comparing it to a vitamin E-synthetic derivative pattern. RESULTS: Among the regional vegetables, it was found that boiled courgettes exhibited the highest antioxidant capability values whereas cucumber had the lowest; on the other hand, vegetables like avocato pear, watercress, cabbage and onion demonstrated higher antioxidant values than those of the same species grown in Cuba. On the contrary, guava, orange and papaya grown in Cuba had the highest antioxidant figures in the fruit group. The best regional foods as to the antioxidant capability were mint and purslane. CONCLUSIONS: It is hoped that the achieved results will contribute to underline the importance of eating those foods whose antioxidant capability protect the body from the action of free radicals causing aging and some diseases.

Características antropométricas, capacidad antioxidante y perfil lipídico sanguíneo de un grupo de mujeres hipertensas de la ciudad de Tuxtla Gutiérrez. Chiapas. México / Anthropometrics characteristics, antioxidant status and lipid seric in hypertension women’s group from Tuxtla Gutierrez city. Chiapas. México

La hipertensión y las dislipidemias son factores de riesgos cardiovasculares que presentan una alta incidencia en México. En el presente trabajo se reportan los datos de un estudio descriptivo de las principales características antropométricas, del perfil lipídico y capacidad antioxidante sanguínea, de un grupo de mujeres hipertensas de la ciudad de Tuxtla Gutiérrez. Para ello se realizaron determinaciones de indicadores antropométricos, de perfil lipídico y capacidad antioxidante total del suero de un grupo de 37 pacientes hipertensas del Hospital Regional de la ciudad de Tuxtla Gutiérrez en Chiapas. México. En el grupo poblacional, el 76 porciento de las pacientes cumplieron con los valores de referencia para el colesterol total y el transportado por las HDL y LDL, pero más de la mitad de ellas presentaron hipertrigliceridemia. Sus capacidades antioxidantes sanguíneas se caracterizaron por valores ligeramente más bajos que los establecidos como referencia para la población europea. En el grupo también se presentaron otros factores de riesgos como la edad y la relación cintura/cadera.