Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation

Abstract

Inducible BALT (iBALT) can amplify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts.

A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression

“…Finally, there was a significant inverse correlation between the number of TLO and the number of Treg ( r 2 = 0.8129, p  = 0.0183) (Figure 8H). Thus, our results are suggesting that numerical changes in Treg and Th1 cells inside TLO are more directly associated with prostate cancer progression or spontaneous regression and are likely showing that besides the role of Treg in modulating local inflammation and adaptive immunity, they are possibly affecting TLO organization during prostate cancer progression (51, 52). …”

Potential of Cells and Cytokines/Chemokines to Regulate Tertiary Lymphoid Structures in Human Diseases

“…CCR7-deficient mice possess few Tregs in lung-draining bronchial lymph nodes suggesting that iBALT formation might be caused by non-functional Treg cells (50). Consistent with this, depletion of Tregs from mice upregulates expression of IL-17A and CXCL9 in the lungs and induces tissue neutrophilia (51). …”

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

“…However, many of the core mechanisms involved in SLO development are also involved in the formation of iBALT. In general, iBALT is formed most easily during the neonatal period in both mice and humans [219,240], perhaps owing to increased frequencies of ILCs or decreased frequencies of Tregs [240,251,252]. In fact, CCR7-deficient mice spontaneously develop iBALT, owing to the inability of Tregs to suppress pulmonary inflammation [251,253,254].…”

“…The formation of iBALT in response to IL-17 involves neutrophil accumulation via the expression of the inflammatory chemokines, CXCL9, CXCL10, and CXCL11 [252,256]. 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].…”