Selectin Ligand-Independent Priming and Maintenance of T Cell Immunity during Airborne Tuberculosis

Schreiber, Tanja; Ehlers, Stefan; Aly, Sahar; Hölscher, Christoph; Hartmann, Sven; Lipp, Martin; Lowe, John B.; Hölscher, Christoph

doi:10.4049/jimmunol.176.2.1131

Cited by 30 publications

(55 citation statements)

References 53 publications

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“…Thus, whereas the frequencies of effector CD8 T cell populations were comparable between WT and FtDKO mice, expression of selectin ligands remains critically important in achieving normal numbers of Ag-specific CD44 high effector CD8 T cells in the LNs following viral infection. These data extend the findings of two previous studies using contact hypersensitivity challenge of skin or intranasal mycobacterial infection of FtDKO mice, showing loss of selectin ligands significantly impairs activated T cell migration to LNs (11,26).…”

Section: Similar Frequency Of Day 8 Ag-specific Effector Cd44 High CDsupporting

confidence: 79%

Memory T Cells Are Enriched in Lymph Nodes of Selectin-Ligand–Deficient Mice

Harp

Gilchrist

Onami

2010

The Journal of Immunology

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Fucosyltransferase-IV and -VII double knockout (FtDKO) mice reveal profound impairment in T cell trafficking to lymph nodes (LNs) due to an inability to synthesize selectin ligands. We observed an increase in the proportion of memory/effector (CD44high) T cells in LNs of FtDKO mice. We infected FtDKO mice with lymphocytic choriomeningitis virus to generate and track Ag-specific CD44highCD8 T cells in secondary lymphoid organs. Although frequencies were similar, total Ag-specific effector CD44highCD8 T cells were significantly reduced in LNs, but not blood, of FtDKO mice at day 8. In contrast, frequencies of Ag-specific memory CD44highCD8 T cells were up to 8-fold higher in LNs of FtDKO mice at day 60. Because wild-type mice treated with anti-CD62L treatment also showed increased frequencies of CD44high T cells in LNs, we hypothesized that memory T cells were preferentially retained in, or preferentially migrated to, FtDKO LNs. We analyzed T cell entry and egress in LNs using adoptive transfer of bone fide naive or memory T cells. Memory T cells were not retained longer in LNs compared with naive T cells; however, T cell exit slowed significantly as T cell numbers declined. Memory T cells were profoundly impaired in entering LNs of FtDKO mice; however, memory T cells exhibited greater homeostatic proliferation in FtDKO mice. These results suggest that memory T cells are enriched in LNs with T cell deficits by several mechanisms, including longer T cell retention and increased homeostatic proliferation.

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Section: Similar Frequency Of Day 8 Ag-specific Effector Cd44 High CDsupporting

confidence: 79%

Memory T Cells Are Enriched in Lymph Nodes of Selectin-Ligand–Deficient Mice

Harp

Gilchrist

Onami

2010

The Journal of Immunology

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“…In murine models of acute antigen-driven lung recruitment, the endothelial selectins E-selectin (CD62E) and P-selectin (CD62P) are required by CD8 T cells, Th1 CD4 T cells and B cells, but not by monocytes, immature DCs, ␥␦ T cells, or Th2 CD4 T cells (58)(59)(60)(61)(62). However, the finding that T-cell recruitment and even germinal center formation in the lungs of mice infected with Mycobacterium tuberculosis are independent of selectin ligand expression (63) implies that chronic infection might induce alternative mechanisms of lung leukocyte recruitment. Expression of selectins and other adhesion molecules on the lung vasculature in COPD is unreported, but important to define, given the imminent availability of therapeutic agents to block this adhesive pathway (64).…”

Section: Lung Inflammation In Copd: Ongoing Recruitment Versus In Sitmentioning

confidence: 95%

The Immunopathogenesis of Chronic Obstructive Pulmonary Disease: Insights from Recent Research

Curtis¹,

Freeman²,

Hogg³

2007

Proceedings of the American Thoracic Society

169

145

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Chronic obstructive pulmonary disease (COPD) progression is characterized by accumulation of inflammatory mucous exudates in the lumens of small airways, and thickening of their walls, which become infiltrated by innate and adaptive inflammatory immune cells. Infiltration of the airways by polymorphonuclear and mononuclear phagocytes and CD4 T cells increases with COPD stage, but the cumulative volume of the infiltrate does not change. By contrast, B cells and CD8 T cells increase in both the extent of their distribution and in accumulated volume, with organization into lymphoid follicles. This chronic lung inflammation is also associated with a tissue repair and remodeling process that determines the ultimate pathologic phenotype of COPD. Why these pathologic abnormalities progress in susceptible individuals, even after removal of the original noxious stimuli, remains mysterious. However, important clues are emerging from analysis of pathologic samples from patients with COPD and from recent discoveries in basic immunology. We consider the following relevant information: normal limitations on the innate immune system's ability to generate adaptive pulmonary immune responses and how they might be overcome by tobacco smoke exposure; the possible contribution of autoimmunity to COPD pathogenesis; and the potential roles of ongoing lymphocyte recruitment versus in situ proliferation, of persistently activated resident lung T cells, and of the newly described T helper 17 (Th17) phenotype. We propose that the severity and course of acute exacerbations of COPD reflects the success of the adaptive immune response in appropriately modulating the innate response to pathogen-related molecular patterns ("the Goldilocks hypothesis").

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“…MTB infection of both humans and mice is associated with pulmonary expression of lymphoid markers and lymphoid-like structures, such as B-cell follicles (Fig. 1) [7,9,10,28]. We have taken a first step in examining the potential functionality of MTB-induced pulmonary lymphoid structures by employing LTbRxSp-deficient mice as a murine model in which conventional lymphoid organs are absent.…”

Section: Discussionmentioning

confidence: 99%

“…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 endothelial venules [4,[7][8][9][10][11]. In a study comparing pathology of human patients with active versus latent TB, presence of lymphoid follicles in granulomatous tissue was associated with immune control whereas absence of such structures was found in patients with active TB disease [12].…”

mentioning

confidence: 99%

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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Selectin Ligand-Independent Priming and Maintenance of T Cell Immunity during Airborne Tuberculosis

Cited by 30 publications

References 53 publications

Memory T Cells Are Enriched in Lymph Nodes of Selectin-Ligand–Deficient Mice

Memory T Cells Are Enriched in Lymph Nodes of Selectin-Ligand–Deficient Mice

The Immunopathogenesis of Chronic Obstructive Pulmonary Disease: Insights from Recent Research

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

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