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

Abstract

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...

CXCR5+ T helper cells mediate protective immunity against tuberculosis

“…Similarly, CXCR5 expression was not required for the expression of Tfh-like markers ICOS and PD-1, production of proinflammatory cytokines, or expression of the Th1 markers Tbet and CXCR3 (data not shown) in CD4 + T cells in our model. This is also consistent with the findings in mice lacking SLOs, which are still able to control Mtb infection and induce effective adaptive T cell responses that presumably prime in the lung (20). That similar numbers of lung myeloid cells accumulate in Cxcr5 -/-Mtb-infected lungs but exhibit reduced activation suggests that absence of CXCR5-mediated T cell localization within the lung results in impaired ability to activate myeloid cells to control intracellular Mtb replication.…”

“…However, CXCL13 is also inducibly expressed in the murine lung following infection with Mtb (18)(19)(20), influenza (6), and in lipopolysaccharide-mediated lung inflammation (21). However, it is not known whether CXCR5 + T cells localize within the lung in response to Mtb infection-induced CXCL13 or whether they play a role in organization of lymphoid structures within TB granulomas and mediate protective immunity.…”

Structure, Organization, and Development of the Mucosal Immune System of the Respiratory Tract

“…For example, mice lacking spleen, lymph nodes, and Peyer's patches generate CD8 T cell responses and isotype-switched B cell responses to influenza with normal kinetics in the lungs (Moyron-Quiroz et al, 2007, 2004. Similar studies using splenectomized LTα-deficient mice, which also lack lymph nodes and Peyer's patches, show that immune responses to pulmonary infection with MTB (Day et al, 2010;Kashino et al, 2010) and Leishmania major antigens (Constant et al, 2002) are intact in the absence of conventional lymphoid organs and that antigen presentation occurs directly in the lung.…”

“…For example, following the induction of BALT by infection with MTB, adoptively transferred ovalbumin (OVA)-specific T cells are primed in the lungs by pulmonary exposure to OVA (Day et al, 2010). Importantly, T cell priming is intact in the lungs of MTB-infected mice that lack conventional secondary lymphoid organs, but does not occur if BALT is not previously induced (Day et al, 2010).…”

Essential role of TNF-alpha in development of spleen fibroblastic reticular cells

“…The generation of immune responses requires the interaction of rare antigen-specific T lymphocytes (T cells) with dendritic cells (DCs) presenting the appropriate antigen [7,8]. This interaction of these two cell types is promoted by specific structures, namely the SLOs [9,10]. SLOs contain several compartments characterized by specific resident stromal cells.…”