ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis

Moguche, Albanus O.; Shafiani, Shahin; Clemons, Corey; Larson, Ryan; Dinh, Crystal; Higdon, Lauren E.; Cambier, C.J.; Sissons, James; Gallegos, Alena M.; Fink, Pamela J.; Urdahl, Kevin B.

doi:10.1084/jem.20141518

Cited by 107 publications

(154 citation statements)

References 57 publications

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“…The expression of genes RBBP8 , RAB13 , FCGR1A , TIMM10 and SMARCD3 has been demonstrated to significantly distinguish between active TB and other diseases such as sarcoidosis and pneumonia (patent WO2014093872 A1). BCL6 has been shown to mediate a sustained Mtb specific CD4 T cell response in addition to regulating host apoptotic responses (Moguche et al, 2015). Both IFI44L and SLPI participate in the interferon-mediated inflammation in TB (Maji et al, 2015), with IFI44L also implicated in lymph node tuberculosis; SLPI has been shown to exhibit antimicrobial activity and also plays an important role in regulating apoptosis by interacting with membrane phospholipid scramblase (Py et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

et al. 2017

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Efficient diagnosis of tuberculosis (TB) is met with multiple challenges, calling for a shift of focus from pathogen-centric diagnostics towards identification of host-based multi-marker signatures. Transcriptomics offer a list of differentially expressed genes, but cannot by itself identify the most influential contributors to the disease phenotype. Here, we describe a computational pipeline that adopts an unbiased approach to identify a biomarker signature. Data from RNA sequencing from whole blood samples of TB patients were integrated with a curated genome-wide molecular interaction network, from which we obtain a comprehensive perspective of variations that occur in the host due to TB. We then implement a sensitive network mining method to shortlist gene candidates that are most central to the disease alterations. We then apply a series of filters that include applicability to multiple publicly available datasets as well as additional validation on independent patient samples, and identify a signature comprising 10 genes — FCGR1A, HK3, RAB13, RBBP8, IFI44L, TIMM10, BCL6, SMARCD3, CYP4F3 and SLPI, that can discriminate between TB and healthy controls as well as distinguish TB from latent tuberculosis and HIV in most cases. The signature has the potential to serve as a diagnostic marker of TB.

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Section: Discussionmentioning

confidence: 99%

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

et al. 2017

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“…In the absence of CXCR5, mice fail to develop iBALT and are more susceptible Mtb (459) with the impaired response being rescued through the adoptive transfer of CXCR5-sufficient T cells, suggesting that CXCR5 expression on T cells is important for both protection and the development of B cell follicles. Further, CXCR5 is required for the maintenance Mtb-specific CD4 + T cells during chronic infection (81). B cells from Mtb infected murine lungs are also able to migrate along a CXCL13 chemotactic gradient in vitro via their expression of CXCR5 (463).…”

Section: The Chemokinesmentioning

confidence: 99%

Cytokines and Chemokines inMycobacterium tuberculosisInfection

et al. 2016

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Chemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells into Mycobacterium tuberculosis -infected lungs. Correct mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. An important block to our understanding of TB pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interplay in light of the conditional role these molecules play throughout infection and disease development. Much of the data highlighted in this review appears at first glance to be contradictory, but it is the balance between the cytokines and chemokines that is critical, and the “goldilocks” (not too much and not too little) phenomenon is paramount in any discussion of the role of these molecules in TB. Determination of how the key chemokines/cytokines and their receptors are balanced and how the loss of that balance can promote disease is vital to understanding TB pathogenesis and to identifying novel therapies for effective eradication of this disease.

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“…In addition, expression of PD-1 and CXCR3 in absence of KLRG-1 facilitates access of these cells to lesions [142]. Such memory-like PD-1 + T cells [143] populate the lesions and are protective in murine TB. Memory CD4 + lymphocytes have been confirmed at the core of human TB granulomas [144] while granulysin/ perforin low-expressing CD8 + T cells populate the outer lymphocyte mantel of granulomas [145].…”

Section: Granuloma: Good For Host and Pathogenmentioning

confidence: 99%

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

2015

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Heightened morbidity and mortality in pulmonary tuberculosis (TB) are consequences of complex disease processes triggered by the causative agent, Mycobacterium tuberculosis (Mtb). Mtb modulates inflammation at distinct stages of its intracellular life. Recognition and phagocytosis, replication in phagosomes and cytosol escape induce tightly regulated release of cytokines [including interleukin (IL)-1, tumor necrosis factor (TNF), IL-10], chemokines, lipid mediators, and type I interferons (IFN-I). Mtb occupies various lung lesions at sites of pathology. Bacteria are barely detectable at foci of lipid pneumonia or in perivascular/bronchiolar cuffs. However, abundant organisms are evident in caseating granulomas and at the cavity wall. Such lesions follow polar trajectories towards fibrosis, encapsulation and mineralization or liquefaction, extensive matrix destruction, and tissue injury. The outcome is determined by immune factors acting in concert. Gradients of cytokines and chemokines (CCR2, CXCR2, CXCR3/CXCR5 agonists; TNF/IL-10, IL-1/IFN-I), expression of activation/death markers on immune cells (TNF receptor 1, PD-1, IL-27 receptor) or abundance of enzymes [arginase-1, matrix metalloprotease (MMP)-1, MMP-8, MMP-9] drive genesis and progression of lesions. Distinct lesions coexist such that inflammation in TB encompasses a spectrum of tissue changes. A better understanding of the multidimensionality of immunopathology in TB will inform novel therapies against this pulmonary disease.

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ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis

Abstract: Protective CD4 T cells specific for M. tuberculosis (Mtb) are maintained in the lungs during active Mtb infection. Similar to memory CD4 T cells, persistence of these Mtb-specific cells requires intrinsic expression of Bcl6 and ICOS.

Cited by 107 publications

References 57 publications

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

Cytokines and Chemokines inMycobacterium tuberculosisInfection

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

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