This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly utilized residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property-specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells. Overall design: 17 samples were analyzed by RNA-Sequencing: 3 replicates of resident memory SMARTA CD4 cells (CD62L- CD69+) from the female reproductive tract (FRT) , 2 replicates of resident memory SMARTA CD4 cells (CD62L- CD69+) from the small intestine epithelium (IEL), 3 replicates of resident memory SMARTA CD4 cells (CD62L- CD69+) small intestine lamina propria (LP), 3 replicates of resident memory SMARTA CD4 cells (CD62L- CD69+) from the spleen (SLO), 3 replicates of SMARTA CD4 cells (CD62L+ CD69- or TCM) from the spleen of mice, and 3 replicates of SMARTA CD4 cells (CD62L- CD69- or TEM) from the spleen of mice infected with LCMV-Armstrong 54 days prior.
CD4<sup>+</sup> resident memory T cells dominate immunosurveillance and orchestrate local recall responses.
Specimen part, Subject
View SamplesWe tested the effects of co-infection on vaccine response to YFV-17D.
Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response.
Specimen part
View SamplesImmunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T cells (TRM) remain parked in nonlymphoid tissues and often stably express CD69. We recently identified TRM within SLO, and this study addresses knowledge gaps in their origin and phenotype. Parabiosis of dirty mice revealed that CD69 expression is insufficient to infer stable residence. Using selective depletion strategies, parabiosis, imaging, tissue grafting, and photoactivatable T cells, we report that restimulation of TRM within the skin or mucosa results in a substantial increase in TRM that patrol all regions of draining lymph nodes. SLO TRM were derived from nonlymphoid tissue residents. Transcriptional profiling and flow cytometry revealed a refined phenotype shared between both nonlymphoid and SLO TRM. These data demonstrate the nonlymphoid origin of SLO TRM and suggest vaccination strategies by which memory CD8 T cell immunosurveillance can be regionalized to specific lymph nodes.
T Cells in Nonlymphoid Tissues Give Rise to Lymph-Node-Resident Memory T Cells.
Specimen part
View SamplesT cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that PD-1 regulates T cell dysfunction during chronic LCMV infection in mice and PD-1 high cells exhibit an intense exhausted gene signature. These findings were extended to human chronic infections such as HIV, HCV and HBV. However, it is not known if PD-1 high cells of healthy humans have the traits of exhausted cells. In this study, we provide a comprehensive description of phenotype, function and gene expression profiles of PD-1 high versus PD-1 low CD8 T cells in the peripheral blood of healthy human adults as following: 1) The percentage of naive and memory CD8 T cells varied widely in the peripheral blood cells of healthy humans and PD-1 was expressed by the memory CD8 T cells. 2) PD-1 high CD8 T cells in healthy humans did not significantly correlated with the PD-1 high exhausted gene signature of HIV specific human CD8 T cells or chronic LCMV specific CD8 T cells from mice. 3) PD-1 expression did not directly affect the ability of CD8 T cells to secrete cytokines in healthy adults. 4) PD-1 was expressed by the effector memory (TEM) compared to terminally differentiated effector (TEMRA) CD8 T cells. 5) Finally, an interesting inverse relationship between CD45RA and PD-1 expression was observed.
Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults.
No sample metadata fields
View SamplesNatural SIV infection of sooty mangabeys (SMs) does not progress to disease despite chronic virus replication. In contrast to pathogenic SIV infection of rhesus macaques (RMs), chronic SIV infection of SMs is characterized by low immune activation. To elucidate the mechanisms underlying this phenotype, we longitudinally assessed host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs is consistently associated with a robust innate immune response, including widespread up-regulation of interferon-stimulated genes (ISGs). Our findings indicate that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low immuneactivation of chronically SIV-infected SMs.
Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys.
Sex, Specimen part
View SamplesTranscriptional Profiling Reveals Distinguishing Features of Immune Activation in the Lymphatic Tissues of Sooty Mangabeys and Rhesus Macaques in Early SIV Infection
Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys.
Specimen part
View SamplesOverexpression of high mobility group AT-hook 2 (HMGA2) associated with truncations of its 3 untranslated region (UTR) with let-7 micro RNA-complementary sequences have been identified in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we generated transgenic mice (Hmga2 mice) with a 3UTR-trncated Hmga2 cDNA that overexpress Hmga2 mRNA and protein in hematopoietic organs. Hmga2 mice showed proliferative hematopoiesis that mimicked a myeloproliferative neoplasm (MPN)-like phenotype with increased numbers of all lineages of peripheral blood cells, hypercellular bone marrow (BM), splenomegaly with extramedullary erythropoiesis, and erythropoietin-independent erythroid colony formation compared to wild-type mice. Hmga2 BM-derived cells took over most of hematopoiesis in competitive repopulations during serial BM transplants. When we bred mice with circulating PNH cells (Piga- mice) with Hmga2 mice, the lack of GPI-linked proteins did not add an additional clonal advantage to the Hmga2+ cells. In summary, our results showed that the overexpression of a 3UTR-truncated Hmga2 leads to a proliferative hematopoiesis with clonal advantage, which may explain clonal expansion in PNH or MPN at the level of HSC.
3'UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice.
Specimen part
View SamplesThe Gata4 transcription factor is essential for normal heart development, but the molecular basis for its function remain poorly understood. We profiled at the whole genome level transcript changes in cardiomyocytes when Gata4 is depleted from zebrafish embryos. Our objective was to elucidate the cardiomyocyte-specific molecular program functioning downstream of Gata4 in order to better understand the role of Gata4 in cardiac morphogenesis. Overall design: Six samples in total are deposited. Three replicate control samples and three replicate Gata4 morphant samples were analyzed.
Small heat shock proteins Hspb7 and Hspb12 regulate early steps of cardiac morphogenesis.
No sample metadata fields
View SamplesThe retinal projection neurons, retinal ganglion cells (RGCs), can be categorized into distinct morphological and functional subtypes and by the laterality of their projections. Here, we used a new method for purifying the sparse population of ipsilaterally projecting RGCs in mouse retina from their contralaterally-projecting counterparts during embryonic development through rapid retrograde labeling followed by fluorescence-activated cell sorting (FACS). Through microarray analysis, we have uncovered the distinct molecular signatures that define and distinguish ipsilateral and contralateral RGCs during the critical period of axonal outgrowth and decussation, with over three hundred genes differentially experienced within these two cell populations. Amongst the genes upregulated in ipsilateral RGCs are many that are known to be expresed in progenitors cells and mark immaturity," including Math5 (Atoh7), Sox2, and cyclin D2. Many of these differentially regulated genes were subsequently validated via in vivo expression analysis. Thus, the molecular signatures of ipsilateral and contralateral RGCs and the mechanisms that regulate their differentiation are more diverse than previously expected.
Ipsilateral and Contralateral Retinal Ganglion Cells Express Distinct Genes during Decussation at the Optic Chiasm.
Specimen part
View SamplesPulmonary alveoli are complex architectural units thought to undergo endogenous or pharmacologically induced programs of regeneration and degeneration. To study the molecular mechanism of alveoli loss mice were calorie restricted at different timepoints. Lungs were harvested and processed for RNA extraction.
Calorie-related rapid onset of alveolar loss, regeneration, and changes in mouse lung gene expression.
Time
View Samples