Damian M. Carragher

The development of inducible bronchus-associated lymphoid tissue depends on IL-17.

Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4+CD3− lymphoid tissue–inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4+ T cells was essential for the formation of iBALT. IL-17 acted by promoting lymphotoxin-α-independent expression of the chemokine CXCL13, which was important for follicle formation. Our results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues.

Ectopic lymphoid tissues and local immunity.

Ectopic or tertiary lymphoid tissues develop at sites of inflammation or infection in peripheral, non-lymphoid organs. These tissues are architecturally similar to conventional secondary lymphoid organs, with separated B and T cell areas, specialized populations of dendritic cells, well-differentiated stromal cells and high endothelial venules. Ectopic lymphoid tissues are often associated with the local pathology that results from chronic infection or chronic inflammation. However, there are also examples in which ectopic lymphoid tissues appear to contribute to local protective immune responses. Here we review how ectopic lymphoid structures develop and function in the context of local immunity and pathology.

Development of secondary lymphoid organs.

Secondary lymphoid organs develop during embryogenesis or in the first few weeks after birth according to a highly coordinated series of interactions between newly emerging hematopoietic cells and immature mesenchymal or stromal cells. These interactions are orchestrated by homeostatic chemokines, cytokines, and growth factors that attract hematopoietic cells to sites of future lymphoid organ development and promote their survival and differentiation. In turn, lymphotoxin-expressing hematopoietic cells trigger the differentiation of stromal and endothelial cells that make up the scaffolding of secondary lymphoid organs. Lymphotoxin signaling also maintains the expression of adhesion molecules and chemokines that govern the ultimate structure and function of secondary lymphoid organs. Here we describe the current paradigm of secondary lymphoid organ development and discuss the subtle differences in the timing, molecular interactions, and cell types involved in the development of each secondary lymphoid organ.

A Novel Role for Non-Neutralizing Antibodies against Nucleoprotein in Facilitating Resistance to Influenza Virus

Current influenza vaccines elicit Abs to the hemagglutinin and neuraminidase envelope proteins. Due to antigenic drift, these vaccines must be reformulated annually to include the envelope proteins predicted to dominate in the following season. By contrast, vaccination with the conserved nucleoprotein (NP) elicits immunity against multiple serotypes (heterosubtypic immunity). NP vaccination is generally thought to convey protection primarily via CD8 effector mechanisms. However, significant titers of anti-NP Abs are also induced, yet the involvement of Abs in protection has largely been disregarded. To investigate how Ab responses might contribute to heterosubtypic immunity, we vaccinated C57BL/6 mice with soluble rNP. This approach induced high titers of NP-specific serum Ab, but only poorly detectable NP-specific T cell responses. Nevertheless, rNP immunization significantly reduced morbidity and viral titers after influenza challenge. Importantly, Ab-deficient mice were not protected by this vaccination strategy. Furthermore, rNP-immune serum could transfer protection to naive hosts in an Ab-dependent manner. Therefore, Ab to conserved, internal viral proteins, such as NP, provides an unexpected, yet important mechanism of protection against influenza. These results suggest that vaccines designed to elicit optimal heterosubtypic immunity to influenza should promote both Ab and T cell responses to conserved internal proteins.

Omental Milky Spots Develop in the Absence of Lymphoid Tissue-Inducer Cells and Support B and T Cell Responses to Peritoneal Antigens

The omentum is a site of B1 cell lymphopoiesis and immune responsiveness to T cell-independent antigens. However, it is unknown whether it supports immune responses independently of conventional lymphoid organs. We showed that the omentum collected antigens and cells from the peritoneal cavity and supported T cell-dependent B cell responses, including isotype switching, somatic hypermutation, and limited affinity maturation, despite the lack of identifiable follicular dendritic cells. The omentum also supported CD4+ and CD8+ T cell responses to peritoneal antigens and recruited effector T cells primed in other locations. Unlike conventional lymphoid organs, milky spots in the omentum developed in the absence of lymphoid tissue-inducer cells, but required the chemokine CXCL13. Although the lymphoid architecture of milky spots was disrupted in lymphotoxin-deficient mice, normal architecture was restored by reconstitution with lymphotoxin-sufficient hematopoietic cells. These results indicate that the milky spots of the omentum function as unique secondary lymphoid organs that promote immunity to peritoneal antigens.

B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms

Immunity to heterosubtypic strains of influenza is thought to be mediated primarily by memory T cells, which recognize epitopes in conserved proteins. However, the involvement of B cells in this process is controversial. We show in this study that influenza-specific memory T cells are insufficient to protect mice against a lethal challenge with a virulent strain of influenza in the absence of B cells. B cells contribute to protection in multiple ways. First, although non-neutralizing Abs by themselves do not provide any protection to challenge infection, they do reduce weight loss, lower viral titers, and promote recovery of mice challenged with a virulent heterosubtypic virus in the presence of memory T cells. Non-neutralizing Abs also facilitate the expansion of responding memory CD8 T cells. Furthermore, in cooperation with memory T cells, naive B cells also promote recovery from infection with a virulent heterosubtypic virus by generating new neutralizing Abs. These data demonstrate that B cells use multiple mechanisms to promote resistance to heterosubtypic strains of influenza and suggest that vaccines that elicit both memory T cells and Abs to conserved epitopes of influenza may be an effective defense against a wide range of influenza serotypes.

The Function of Local Lymphoid Tissues in Pulmonary Immune Responses

Primary adaptive immune responses are initiated in secondary lymphoid organs, such as spleen, lymph nodes, and Peyer’s patches. These lymphoid organs recruit naive lymphocytes1 as well as activated antigen-presenting cells (APCs)2, and facilitate lymphocyte activation, expansion, and differentiation. For example, infection of the lung with influenza virus leads to activation of pulmonary dendritic cells, which engulf local antigens and traffic to the draining mediastinal lymph node (MLN)3, where they home to the T cell area surrounding the high endothelial venules (HEVs) (Figure 1). Naive B and T cells are constantly recruited into the lymph node via these HEVs and rapidly become activated as they encounter cognate antigen on APCs. Activated lymphocytes subsequently expand and differentiate into effector cells. For T cells, this differentiation primarily occurs in the T cell zone. In contrast, B cells rapidly expand and are selected for high-affinity variants in the germinal centers (GCs) that develop on the border between the T cell area and the B cell follicle. As the immune response progresses, effector B and T cells leave the lymph node via the efferent lymphatics, which drain into the blood via the thoracic duct. Once in the blood, activated effector cells recirculate to sites of inflammation, including the original site of infection in the lung, and use their effector functions to combat infection. An important point of this model is that, while infection occurs locally in non-lymphoid organs, primary immune responses are initiated centrally in secondary lymphoid organs. This scheme is outlined in Figure 1.

Induction of BALT in the absence of IL-17

volume 13 number 1 january 2012 nature immunology outcomes9,10, particularly those associated with inflammatory diseases. Similarly, differences in commensal colonization may alter the number or repertoire of regulatory T cells, which are also known to affect the formation of iBALT11. In summary, the results of Fleige et al. have clearly demonstrated that ectopic follicles such as iBALT can form independently of IL-17 in response to some types of inflammatory triggers. Nevertheless, we stand by our data showing that IL-17 is essential for iBALT formation in response to LPS-mediated inflammation, and we believe that IL-17mediated induction of CXCL13 expression is a common mechanism for the formation of ectopic follicles in response to bacterial infection as well as in a variety of autoimmune and inflammatory diseases.