38 research outputs found
Memory CD8<sup>+</sup> T cells exhibit tissue imprinting and non-stable exposure-dependent reactivation characteristics following blood-stage Plasmodium berghei ANKA infections
Experimental cerebral malaria (ECM) is a severe complication of Plasmodium berghei ANKA (PbA) infection in mice, characterized by CD8(+) Tācell accumulation within the brain. Whilst the dynamics of CD8(+) Tācell activation and migration during extant primary PbA infection have been extensively researched, the fate of the parasiteāspecific CD8(+) T cells upon resolution of ECM is not understood. In this study, we show that memory OTāI cells persist systemically within the spleen, lung and brain following recovery from ECM after primary PbAāOVA infection. Whereas memory OTāI cells within the spleen and lung exhibited canonical central memory (Tcm) and effector memory (Tem) phenotypes, respectively, memory OTāI cells within the brain postāPbAāOVA infection displayed an enriched CD69(+)CD103(ā) profile and expressed low levels of Tābet. OTāI cells within the brain were excluded from shortāterm intravascular antibody labelling but were targeted effectively by longerāterm systemically administered antibodies. Thus, the memory OTāI cells were extravascular within the brain postāECM but were potentially not resident memory cells. Importantly, whilst memory OTāI cells exhibited strong reactivation during secondary PbAāOVA infection, preventing activation of new primary effector T cells, they had dampened reactivation during a fourth PbAāOVA infection. Overall, our results demonstrate that memory CD8(+) T cells are systemically distributed but exhibit a unique phenotype within the brain postāECM, and that their reactivation characteristics are shaped by infection history. Our results raise important questions regarding the role of distinct memory CD8(+) Tācell populations within the brain and other tissues during repeat Plasmodium infections
Memory CD8 + T cells exhibit tissue imprinting and nonāstable exposureādependent reactivation characteristics following bloodāstage Plasmodium berghei ANKA infections
From Wiley via Jisc Publications RouterHistory: received 2020-11-02, rev-recd 2021-08-09, accepted 2021-08-13, pub-electronic 2021-08-27Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): G0900487, MR/R010099/1Abstract: Experimental cerebral malaria (ECM) is a severe complication of Plasmodium berghei ANKA (PbA) infection in mice, characterized by CD8+ Tācell accumulation within the brain. Whilst the dynamics of CD8+ Tācell activation and migration during extant primary PbA infection have been extensively researched, the fate of the parasiteāspecific CD8+ T cells upon resolution of ECM is not understood. In this study, we show that memory OTāI cells persist systemically within the spleen, lung and brain following recovery from ECM after primary PbAāOVA infection. Whereas memory OTāI cells within the spleen and lung exhibited canonical central memory (Tcm) and effector memory (Tem) phenotypes, respectively, memory OTāI cells within the brain postāPbAāOVA infection displayed an enriched CD69+CD103ā profile and expressed low levels of Tābet. OTāI cells within the brain were excluded from shortāterm intravascular antibody labelling but were targeted effectively by longerāterm systemically administered antibodies. Thus, the memory OTāI cells were extravascular within the brain postāECM but were potentially not resident memory cells. Importantly, whilst memory OTāI cells exhibited strong reactivation during secondary PbAāOVA infection, preventing activation of new primary effector T cells, they had dampened reactivation during a fourth PbAāOVA infection. Overall, our results demonstrate that memory CD8+ T cells are systemically distributed but exhibit a unique phenotype within the brain postāECM, and that their reactivation characteristics are shaped by infection history. Our results raise important questions regarding the role of distinct memory CD8+ Tācell populations within the brain and other tissues during repeat Plasmodium infections
Comparison of CD8(+) T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria
Long-lived CD4+IFN-Ī³+ T cells rather than short-lived CD4<sup>+</sup>IFN-Ī³<sup>+</sup>IL-10<sup>+</sup> T cells initiate rapid IL-10 production to suppress anamnestic T cell responses during secondary malaria infection
CD4(+) T cells that produce IFN-Ī³ are the source of host-protective IL-10 during primary infection with a number of different pathogens, including Plasmodium spp. The fate of these CD4(+)IFN-Ī³(+)IL-10(+) T cells following clearance of primary infection and their subsequent influence on the course of repeated infections is, however, presently unknown. In this study, utilizing IFN-Ī³āyellow fluorescent protein (YFP) and IL-10āGFP dual reporter mice, we show that primary malaria infectionāinduced CD4(+)YFP(+)GFP(+) T cells have limited memory potential, do not stably express IL-10, and are disproportionately lost from the Ag-experienced CD4(+) T cell memory population during the maintenance phase postinfection. CD4(+)YFP(+)GFP(+) T cells generally exhibited a short-lived effector rather than effector memory T cell phenotype postinfection and expressed high levels of PD-1, Lag-3, and TIGIT, indicative of cellular exhaustion. Consistently, the surviving CD4(+)YFP(+)GFP(+) T cellāderived cells were unresponsive and failed to proliferate during the early phase of secondary infection. In contrast, CD4(+)YFP(+)GFP(ā) T cellāderived cells expanded rapidly and upregulated IL-10 expression during secondary infection. Correspondingly, CD4(+) T cells were the major producers within an accelerated and amplified IL-10 response during the early stage of secondary malaria infection. Notably, IL-10 exerted quantitatively stronger regulatory effects on innate and CD4(+) T cell responses during primary and secondary infections, respectively. The results in this study significantly improve our understanding of the durability of IL-10āproducing CD4(+) T cells postinfection and provide information on how IL-10 may contribute to optimized parasite control and prevention of immune-mediated pathology during repeated malaria infections
Parasite-specific CD4+IFN-Ī³+IL-10+ T cells distribute within both lymphoid and non-lymphoid compartments and are controlled systemically by IL-27 and ICOS during blood-stage malaria infection.
Immune-mediated pathology in interleukin-10 (IL-10)-deficient mice during blood-stage malaria infection typically manifests in nonlymphoid organs, such as the liver and lung. Thus, it is critical to define the cellular sources of IL-10 in these sensitive nonlymphoid compartments during infection. Moreover, it is important to determine if IL-10 production is controlled through conserved or disparate molecular programs in distinct anatomical locations during malaria infection, as this may enable spatiotemporal tuning of the regulatory immune response. In this study, using dual gamma interferon (IFN-Ī³)āyellow fluorescent protein (YFP) and IL-10āgreen fluorescent protein (GFP) reporter mice, we show that CD4(+) YFP(+) T cells are the major source of IL-10 in both lymphoid and nonlymphoid compartments throughout the course of blood-stage Plasmodium yoelii infection. Mature splenic CD4(+) YFP(+) GFP(+) T cells, which preferentially expressed high levels of CCR5, were capable of migrating to and seeding the nonlymphoid tissues, indicating that the systemically distributed host-protective cells have a common developmental history. Despite exhibiting comparable phenotypes, CD4(+) YFP(+) GFP(+) T cells from the liver and lung produced significantly larger quantities of IL-10 than their splenic counterparts, showing that the CD4(+) YFP(+) GFP(+) T cells exert graded functions in distinct tissue locations during infection. Unexpectedly, given the unique environmental conditions within discrete nonlymphoid and lymphoid organs, we show that IL-10 production by CD4(+) YFP(+) T cells is controlled systemically during malaria infection through IL-27 receptor signaling that is supported after CD4(+) T cell priming by ICOS signaling. The results in this study substantially improve our understanding of the systemic IL-10 response to malaria infection, particularly within sensitive nonlymphoid organs
Gamma Interferon Mediates Experimental Cerebral Malaria by Signaling within Both the Hematopoietic and Nonhematopoietic Compartments
Memory CD8+ T cells exhibit tissue imprinting and nonstable exposure-dependent reactivation characteristics following blood-stage Plasmodium berghei ANKA infections
Tissue-resident macrophages in the intestine are long-lived and defined by Tim-4 and CD4 expression
Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer's disease
The brain microcirculation is increasingly viewed as a potential target for disease-modifying drugs in the treatment of Alzheimerās disease patients, reflecting a growing appreciation of evidence that cerebral blood flow is compromised in such patients. However, the pathogenic mechanisms in brain resistance arteries underlying blood flow defects have not yet been elucidated. Here we probed the roles of principal vasodilatory pathways in cerebral arteries using the APP23 mouse model of Alzheimerās disease, in which amyloid precursor protein is increased approximately sevenfold, leading to neuritic plaques and cerebrovascular accumulation of amyloid-Ī² similar to those in patients with Alzheimerās disease. Pial arteries from APP23 mice (18 mo old) exhibited enhanced pressure-induced (myogenic) constriction because of a profound reduction in ryanodine receptor-mediated, local calcium-release events (āCa(2+) sparksā) in arterial smooth muscle cells and a consequent decrease in the activity of large-conductance Ca(2+)-activated K(+) (BK) channels. The ability of the endothelial cell inward rectifier K(+) (Kir2.1) channel to cause dilation was also compromised. Acute application of amyloid-Ī² 1-40 peptide to cerebral arteries from wild-type mice partially recapitulated the BK dysfunction seen in APP23 mice but had no effect on Kir2.1 function. If mirrored in human Alzheimerās disease, these tandem defects in K(+) channel-mediated vasodilation could account for the clinical cerebrovascular presentation seen in patients: reduced blood flow and crippled functional hyperemia. These data direct future research toward approaches that reverse this dual vascular channel dysfunction, with the ultimate aim of restoring healthy cerebral blood flow and improving clinical outcomes