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Gene expression profiling of granuloma T cells in M. tuberculosis infected rhesus macaques reveals a critical role for CD30 [Macaca mulatta]

ABSTRACT: Control of Mycobacterium tuberculosis infection requires generation of T cells that migrate to granulomas, complex immune structures surrounding sites of bacterial replication. Here we compared the gene expression profiles of T cells in pulmonary granulomas, bronchoalveolar lavage and blood of Mtb-infected rhesus macaques to identify granuloma-enriched T cell genes. TNFRSF8/CD30 was among the top genes that was upregulated in both CD4 and CD8 granuloma T cells and independent of bacterial loads. Transcriptomic profiling of lung T cells from Mtb-infected mixed bone marrow chimeric mice showed that CD30 directly promotes CD4 T cell differentiation and effector molecule expression. Moreover, in mice CD30 expression on CD4 T cells is required for survival of Mtb infection. These results show the CD30 co-stimulatory axis is highly upregulated on granuloma T cells and is critical for the generation of protective T cell responses against Mtb infection.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE227653 | GEO | 2023/03/22

REPOSITORIES: GEO

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Gene expression profiling of granuloma T cells in M. tuberculosis infected rhesus macaques reveals a critical role for CD30 [Mus musculus]

Project description:Control of Mycobacterium tuberculosis infection requires generation of T cells that migrate to granulomas, complex immune structures surrounding sites of bacterial replication. Here we compared the gene expression profiles of T cells in pulmonary granulomas, bronchoalveolar lavage and blood of Mtb-infected rhesus macaques to identify granuloma-enriched T cell genes. TNFRSF8/CD30 was among the top genes that was upregulated in both CD4 and CD8 granuloma T cells and independent of bacterial loads. Transcriptomic profiling of lung T cells from Mtb-infected mixed bone marrow chimeric mice showed that CD30 directly promotes CD4 T cell differentiation and effector molecule expression. Moreover, in mice CD30 expression on CD4 T cells is required for survival of Mtb infection. These results show the CD30 co-stimulatory axis is highly upregulated on granuloma T cells and is critical for the generation of protective T cell responses against Mtb infection.

2023-03-24 | GSE228113 | GEO

Lymphoid function of the tuberculous granuloma

Project description:Induced lymphoid structures associated with pulmonary granulomas have been observed during TB in both humans and mice and could orchestrate host defense. In order to determine whether granulomas perform lymphoid functions, mice lacking secondary lymphoid organs (SLOs) were infected with Mycobacterium tuberculosis (MTB). As in wild type mice (WT), granulomas developed, MTB was controlled, and antigen-specific T cell responses including T central memory (TCM) cells were generated in the complete absence of SLOs. Moreover, T cell activation correlated with granuloma formation in these mice and TCM cells accumulated in lungs and participated in protection against secondary MTB infection. Lung granulomas may therefore represent tertiary lymphoid organs (TLOs) capable of priming robust T cell responses and mediating host defense during chronic MTB at the site of infection.

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Direct comparison of HES2 ESC overexpressing CD30 variant with HES2 overexpressing GFP

Project description:HES2 ESC were infected with a lentivirus construct containing either CD30 (TNFRSF8) extracellular deficient variant or GFP, using the ViraPower™ Promoterless Lentiviral Gateway® Kits (Invitrogen). HES2 cells were recovered and grown for 19 passages. HES2 were commonly grown on Mouse Embryonic Feeder cells in the presence of KSOR media. Before collection of RNA, ES cells were FACs sorted with antibodies to GCMT-2 and CD9 to separate ES cells from differentiated cells and mouse feeders. The experiment was repeated in triplicate. The final aim was to deduce the effect of overexpressing the variant form of CD30 on gene expression in HES2 cells.

2009-10-10 | GSE13261 | GEO

Direct comparison of HES2 ESC overexpressing CD30 variant with HES2 overexpressing GFP

Project description:HES2 ESC were infected with a lentivirus construct containing either CD30 (TNFRSF8) extracellular deficient variant or GFP, using the ViraPowerâ?¢ Promoterless Lentiviral GatewayÂ® Kits (Invitrogen). HES2 cells were recovered and grown for 19 passages. HES2 were commonly grown on Mouse Embryonic Feeder cells in the presence of KSOR media. Before collection of RNA, ES cells were FACs sorted with antibodies to GCMT-2 and CD9 to separate ES cells from differentiated cells and mouse feeders. The experiment was repeated in triplicate. The final aim was to deduce the effect of overexpressing the variant form of CD30 on gene expression in HES2 cells. Three consecutive passages of HES2 cells over-expressing either CD30V or GFP were grown and subject to FACs sorting, collection and microarray. A total of 6 samples, (3 replicates of these 2 populations) were used in the experiment.

2010-04-08 | E-GEOD-13261 | biostudies-arrayexpress

CD153 expression by CD4 T cells is required for control of pulmonary Mycobacterium tuberculosis infection

Project description:Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and among the top ten causes of all human death worldwide1. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFN production is the primary mechanism of CD4 T cell-mediated protection2,3. However, IFN responses do not correlate with host protection, and several reports have demonstrated that additional anti-tuberculous CD4 T cell effector functions remain unaccounted for4-8. Here we show that the TNF superfamily molecule CD153 (TNFSF8) is required for IFN-independent control of pulmonary Mtb infection by CD4 T cells. In Mtb infected mice, CD153 expression is highest on Ag-specific Th1 cells in the lung tissue parenchyma, but its induction does not require Th1 polarization. CD153 deficient mice develop high pulmonary but not splenic bacterial loads and succumb early to Mtb infection. Reconstitution of T cell-deficient hosts with either CD153-/- or IFN-/- CD4 T cells fails to rescue mice from early mortality, but reconstitution with a mixture of CD153-/- and IFN-/- CD4 T cells provides similar protection as WT T cells. In Mtb infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to the blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active TB. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, we have identified expression of CD153 by CD4 T cells as a major immune mechanism of host protection against pulmonary Mtb infection.

2018-07-10 | GSE116830 | GEO

Ultra-low dose aerosol infection provides an improved murine model of tuberculosis

Project description:Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the mouse TB model and show that ULD infection recapitulates key features of human TB.

2020-11-06 | GSE158807 | GEO

A protective role for eosinophils in host resistance to Mycobacterium tuberculosis

Project description:Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis (TB) are incompletely understood. Here we show a role for eosinophils in host resistance to Mtb infection. In humans, eosinophils are found in resected human TB lung lesions and autopsy granulomas. Eosinophils are also found in granulomas in zebrafish, mice, and non-human primates, where they are functionally activated and degranulate. Transcriptional profiling of lung tissue after Mtb infection of mice, that selectively lack eosinophils, revealed changes in neuronal associated pathways. Importantly, employing several independent models of eosinophil deficiency in mice, we demonstrate that eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings establish an unexpected role for eosinophils, granulocytes typically associated with type II inflammation, in host resistance against Mtb, a major human bacterial pathogen.

2021-08-01 | GSE165871 | GEO

A serine protease inhibitor induces necrosis of infected macrophages within granulomas during activation of tuberculosis

Project description:Granulomas function in humans during tuberculosis by focusing production of host antimicrobial factors against the causative bacterial agent Mycobacterium tuberculosis to contain infection. We show that mice unable to produce nitric oxide –itself an important antimicrobial molecule- demonstrate functional granulomas in the lung able to control infection after dermal infection. Disease in the lung was activated by administration of neutralising antibody against either TNF-α, which disrupted granuloma integrity, or INF-γ, which resulted in development of caseous necrosis within granulomas reminiscent of active human tuberculosis. In the latter case, the serpin protease inhibitor serpinb3a and its target protease, cathepsin G are highly expressed in cells local to necrotic regions in granulomas and serpinb3a induces necrosis of infected macrophages independently of cathepsin G binding. Therefore a single host protein is capable of inducing necrosis and bacterial growth during intracellular infection.

2010-12-22 | GSE14826 | GEO

Gene expression profiles of caseous human pulmonary TB granulomas derived from TB patients

2010-06-02 | GSE20050 | GEO

Gene expression profiles of caseous human pulmonary TB granulomas derived from TB patients

Project description:Most individuals infected with Mycobacterium tuberculosis can control the infection by forming and maintaining TB granulomas at the local infection foci. However, when the chronic infection (also known as latency) becomes active, the caseous center of TB granuloma enlarges, and it liquefies and cavitates, ultimately releasing bacilli into airway. Deciphering how genes are regulated within TB granulomas will help to understand the granuloma biology. Therefore, we performed genome-wide microarray on caseous human pulmonary TB granulomas and compared with normal lung tissues. Laser capture microdissection (LCM) was used to dissect out caseous granulomas from TB patients' lung tissues, excluding uninvolved areas. Total RNA were isolated from LCM-derived materials and used for microarray. As a control, parenchyma from normal lung tissues was prepared in the same manner as caseous granulomas. Sample GSM501252, Caseum 2-C, is missing a CEL file.

2010-06-08 | E-GEOD-20050 | biostudies-arrayexpress

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