ESAT-6-specific CD4 T cell responses to aerosol<i>Mycobacterium tuberculosis</i>infection are initiated in the mediastinal lymph nodes

Reiley, William W.; Calayag, Mark; Wittmer, Susan; Huntington, Jennifer L.; Pearl, John E.; Fountain, Jeffrey J.; Martino, Cynthia A.; Roberts, Alan D.; Cooper, Andrea M.; Winslow, Gary M.; Woodland, David L.

doi:10.1073/pnas.0801496105

Cited by 200 publications

(222 citation statements)

References 30 publications

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Section: Normal T-cell Development Without Slomentioning

confidence: 89%

“…and in LTbR-and LTbRxSp-deficient mice by days 38 and 45, respectively (Fig 5C and D). Because CD69 is rapidly down-regulated upon egress from LN and was restricted to mediastinal LN T cells early during MTB infection, these data suggest that T cells may be primed locally in lungs at later stages of infection in WT and LTbR-deficient mice [22]. To verify whether T-cell priming outside of SLO induced a complete effector T-cell developmental program, we examined expression of CD27, a surface marker which is down-regulated on terminally differentiated effector T cells.…”

Section: Normal T-cell Development Without Slomentioning

confidence: 89%

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Secondary lymphoid organs are dispensable for the development of T‐cell‐mediated immunity during tuberculosis

et al. 2010

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Tuberculosis causes 2 million deaths per year, yet in most cases the immune response successfully contains the infection and prevents disease outbreak. Induced lymphoid structures associated with pulmonary granuloma are observed during tuberculosis in both humans and mice and could orchestrate host defense. To investigate whether granuloma perform lymphoid functions, mice lacking secondary lymphoid organs (SLO) were infected with Mycobacterium tuberculosis (MTB). As in WT mice, granuloma developed, exponential growth of MTB was controlled, and antigen-specific T-cell responses including memory T cells were generated in the absence of SLO. Moreover, adoptively transferred T cells were primed locally in lungs in a granuloma-dependent manner. T-cell activation was delayed in the absence of SLO, but resulted in a normal development program including protective subsets and functional recall responses that protected mice against secondary MTB infection. Our data demonstrate that protective immune responses can be generated independently of SLO during MTB infection and implicate local pulmonary T-cell priming as a mechanism contributing to host defense.Key words: Granuloma . Lymphoid neogenesis . T-cell development . Tuberculosis Supporting Information available online IntroductionMycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), currently persists in one-third of the world's population [1]. In most cases, the immune response generated upon exposure contains, but does not eradicate, the bacilli and an asymptomatic persistent infection develops, termed latent TB. Approximately one in ten latently infected individuals undergo reactivation to active TB disease during their lifetime. However, Ã These authors contributed equally to this work. ÃÃ These authors share equal senior authorship. [2,3]. Granuloma are considered central for control of MTB as loss of granuloma structure is associated with poor disease outcome in humans and animal models [3,4]. Yet, the precise mechanisms by which granuloma mediate control of MTB are poorly understood. Induction of an adaptive immune response is essential for host protection against MTB. Antigen-specific T-cell responses are generated within secondary lymphoid organs (SLO), such as lymph nodes (NO) and spleen. SLO maximize efficiency of encounters between APC and naïve T lymphocytes [5]. Therefore, SLO are critical for the generation of adaptive immunity. Ectopic accumulations of lymphoid cells, known as tertiary lymphoid organs, sometimes arise during chronic inflammation or infection. Tertiary lymphoid organs resemble SLO in structure and cell composition and evidence exists that some are capable of generating adaptive immunity [5,6]. However, whether immune responses generated outside of SLO are truly effective and thus beneficial in defense against pathogens is unclear.Recent reports have described lymphoid features associated with murine and human granuloma, such as B-cell follicles and the peripheral node addressin, which is expressed on high endothel...

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Section: Normal T-cell Development Without Slomentioning

confidence: 89%

Section: Normal T-cell Development Without Slomentioning

confidence: 89%

Secondary lymphoid organs are dispensable for the development of T‐cell‐mediated immunity during tuberculosis

et al. 2010

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“…Immune response to MTB infection is primarily mediated by T cells (Lockhart et al 2006). In previous research of human pulmonary TB, T cells responding to ESAT-6 are observed in approximately half of the patients (Guinn et al 2004;Reiley et al 2008). ESAT-6, a vital immune-dominant antigen encoded by region of difference-1 (RD1) and RD2, has been reported to have the potential for human MTB diagnosis (Sang and Zhang 2012;Li et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Early Diagnosis of Tuberculosis-Associated IgA Nephropathy with ESAT-6

Zhao

Sun

et al. 2017

Tohoku J. Exp. Med.

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IgA nephropathy (IgAN) is the most common cause of primary renal diseases worldwide, and the early secreted antigenic target of 6 (ESAT-6) which was secreted by Mycobacterium tuberculosis (MTB) may be involved in the development and progression of IgAN. This study aimed to investigate the role of ESAT-6 for early diagnosis of IgAN caused by MTB infection. From 2011 to 2014, 21 patients with renal tuberculosis (RTB), 25 with IgAN, and 46 with IgAN infected with MTB (IgAN/MTB) were enrolled. Serum levels of antibodies against Mycobacterium tuberculosis antigen 85A (Ag85A) were measured by ELISA. Urine culture and phage amplified biologically assay were performed to detect MTB. HE staining was used to observe the morphological changes in kidney tissues. Immunohistochemistry was applied to detect the expression of ESAT-6. Immunofluorescence staining was conducted to detect IgA1. Positive rates of serum anti-Ag85A antibody and urine culture for MTB were higher in the RTB and IgAN/MTB groups than those in the IgAN group. The positive rates of plaques were also higher in RTB and IgAN/MTB groups than the positive rate in the IgAN group. By contrast, the positive rate of ESAT-6 was lower in the IgAN group than that in the RTB group or the IgAN/MTB group, whereas the expression levels of IgA1 were higher in the IgAN and IgAN/MTB groups, compared with the RTB group. Our findings suggest that ESAT-6 and IgA1 may be helpful for early diagnosis of IgAN caused by MTB infection.

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“…Lymphocytes isolated from infected mice were incubated in a 96-well plate, at a concentration of 3 × 10 6 cells per well. Cells were incubated in the presence of ESAT-6 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] or Sendai HN [421][422][423][424][425][426][427][428][429][430][431][432][433][434][435][436] peptide (5 μg/mL each) for 2 h at 37°C; Brefeldin A (50 μg/mL) was added, and the incubation was continued for an additional 4 h. Surface staining for CD4, CD8, PD-1, and KLRG1 was performed, as described previously (22), and the cells were fixed and permeabilized using a Cytofix/Cytoperm Fixation/ Permeabilization kit (BD Biosciences). For detection of intracellular IFNγ and TNFα, the cells were incubated for 30 min in Perm/Wash Buffer (BD Biosciences) with anti-IFNγ (clone XMG1.2) and anti-TNFα (clone MP6-XT22); the cells were analyzed as described above.…”

Section: Methodsmentioning

confidence: 99%

Distinct functions of antigen-specific CD4 T cells during murineMycobacterium tuberculosisinfection

Reiley

Shafiani

Wittmer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The immune response elicited after Mycobacterium tuberculosis (Mtb) infection is critically dependent on CD4 T cells during both acute and chronic infection. How CD4 T-cell responses are maintained throughout infection is not well understood, and evidence from other infection models has suggested that, under conditions of chronic antigen stimulation, T cells can undergo replicative exhaustion. These findings led us to determine whether subpopulations of CD4 T cells existed that displayed markers of terminal differentiation or exhaustion during murine Mtb infection. Analysis of antigen-specific effector CD4 T cells revealed that programmed death-1 (PD-1) and the killer cell lectin-like receptor G1 (KLRG1) delineated subpopulations of T cells. PD-1-expressing CD4 T cells were highly proliferative, whereas KLRG1 cells exhibited a short lifespan and secreted the cytokines IFNγ and TNFα. Adoptive transfer studies demonstrated that proliferating PD-1-positive CD4 T cells differentiated into cytokine-secreting KLRG1-positive T cells, but not vice versa. Thus, proliferating PD-1-positive cells are not exhausted, but appear to be central to maintaining antigen-specific effector T cells during chronic Mtb infection. Our findings suggest that antigen-specific T-cell responses are maintained during chronic mycobacterial infection through the continual production of terminal effector cells from a proliferating precursor population.T uberculosis presents a challenging worldwide public heath problem. Infection with Mycobacterium tuberculosis (Mtb) elicits humoral and cellular immune responses that normally control bacterial burden. However, bacteria are seldom, if ever, eradicated, and control of the infection requires continual effector T-cell responses. Consequently, either the depletion or suppression of T-cell responses results in disease reactivation (1). In the mouse model, Mtb causes chronic infection and control of infection is maintained by T cells essentially indefinitely (2).Although a sustained T-cell response against Mtb infection is necessary, it is not understood how effector T cells are maintained. We have previously demonstrated that CD4 T-cell responses are associated with extensive proliferation throughout Mtb infection (3), suggesting that proliferation is a major mechanism required for the maintenance of T-cell responses. However, it is not clear how T-cell proliferation can be maintained during chronic infection, especially because effector T cells have been described to have a limited capacity for self-renewal (4).Although the numbers of antigen-specific T cells are relatively stable during chronic Mtb infection, CD4 T cells proliferate extensively, suggesting that a high turnover of effector CD4 T cells occurs. This high level of turnover suggests that effector T cells become exhausted or terminally differentiated, and that the maintenance of the T-cell response depends on the continual replacement of effector T cells. The expression of several cellsurface receptors has been correlated with functional e...

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ESAT-6-specific CD4 T cell responses to aerosolMycobacterium tuberculosisinfection are initiated in the mediastinal lymph nodes

Cited by 200 publications

References 30 publications

Secondary lymphoid organs are dispensable for the development of T‐cell‐mediated immunity during tuberculosis

Secondary lymphoid organs are dispensable for the development of T‐cell‐mediated immunity during tuberculosis

Early Diagnosis of Tuberculosis-Associated IgA Nephropathy with ESAT-6

Distinct functions of antigen-specific CD4 T cells during murineMycobacterium tuberculosisinfection

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