Pneumocystis -Driven Inducible Bronchus-Associated Lymphoid Tissue Formation Requires Th2 and Th17 Immunity

Abstract

Summary Inducible bronchus associated lymphoid tissue (iBALT) is an ectopic lymphoid structure composed of highly organized T-cell and B-cell zones that forms in the lung in response to infectious or inflammatory stimuli. Here, develop a model for fungal-mediated iBALT formation, using infection with Pneumocystis which induces development of pulmonary lymphoid follicles. Pneumocystis-dependent iBALT structure formation and organization required CXCL13 signaling. Cxcl13 expression was regulated by IL-17 family members, as Il17ra−/−, Il17rb−/−, and Il17rc−/− mice failed to develop iBALT. Interestingly, Il17rb−/− mice have intact Th17 responses, but failed to generate an anti-Pneumocystis Th2 response. Given a role for Th2 and Th17 immunity in iBALT formation, we demonstrated that primary pulmonary fibroblasts synergistically upregulated Cxcl13 transcription following dual stimulation with IL-13 and IL-17A in a STAT3/GATA3 dependent manner. Together, these findings uncover a role for Th2/Th17 cells in regulating Cxcl13 expression and provide an experimental model for fungal-driven iBALT formation.

New advances in understanding the host immune response to Pneumocystis

“…Therefore, a consequence of chronic exposure to Pneumocystis could indeed be asthma. A recent study has also linked the Pneumocystis -driven Th2 response to inducible bronchus associated lymphoid tissue (iBALT) [40]. iBALT, is a lymphoid structure which forms in response to infectious stimuli and often associated with chronic diseases, such as rheumatoid arthritis, tuberculosis and chronic obstructive pulmonary disease (COPD).…”

Anatomical Uniqueness of the Mucosal Immune System (GALT, NALT, iBALT) for the Induction and Regulation of Mucosal Immunity and Tolerance

“…Neutrophils and other granulocytes cause damage, in part because of the release of proteases [257À259], which trigger the expression of homeostatic and inflammatory chemokines and lead to iBALT formation [259]. Similarly, IL-17 directly promotes the expression of the homeostatic chemokines CXCL13 and CCL19 [240,260,261], which are important for the recruitment of B and T cells and for the formation of iBALT. Although IL-17 promotes the expression of these chemokines under inflammatory conditions, lymphotoxin signaling maintains the expression of these chemokines under homeostatic conditions [240,241,261].…”

“…Similarly, IL-17 directly promotes the expression of the homeostatic chemokines CXCL13 and CCL19 [240,260,261], which are important for the recruitment of B and T cells and for the formation of iBALT. Although IL-17 promotes the expression of these chemokines under inflammatory conditions, lymphotoxin signaling maintains the expression of these chemokines under homeostatic conditions [240,241,261]. Thus once iBALT is formed, it no longer requires IL-17 but instead requires lymphotoxin-expressing lymphocytes and DCs to maintain stromal architecture, chemokine expression, and HEV differentiation.…”

“…For example, pulmonary exposure to alum or silica particles trigger dying macrophages to release IL-1α, which acts as an alarmin that promotes the recruitment of eosinophils, macrophages, neutrophils, DCs, and T cells to the lungs and ultimately leads to iBALT formation [262]. In another example, pulmonary infection with Pneumocystis murina elicits the expression of IL-25 and IL-17, which indirectly trigger the expression of CXCL13 by lung fibroblasts via IL-13 and IL-6 [261]. Interestingly, the IL-25 and IL-17 receptor complexes share a common subunit, the IL-17Rα [263,264].…”

Tertiary lymphoid tissue develops during normal aging in mice and humans

“…However, non-lymphoid tissues may form ectopic SLO-like 55 structures, known as tertiary lymphoid tissues (TLTs), in response to chronic inflammation and 56 antigen exposure (21,22). Aging affects the size, presence, and functionality of TLTs in several 57 tissues (23)(24)(25)(26). For example, isolated lymphoid follicles (intestinal TLT) in aged mice have altered 58 cellular compositions and produce more IgA compared to young mice (27), and inducible 59 bronchus-associated lymphoid tissue (lung TLT) forms more robustly in response to cigarette 60 smoke in aged mice compared to young mice (28).…”