Abstract
Soluble tumor necrosis factor (sTNF) is an important inflammatory mediator and essential for secondary lymphoid organ (SLO) development and function. However, the role of its transmembrane counterpart (tmTNF) in these processes is less well established. Here, the effects of tmTNF overxpression on SLO architecture and function were investigated using tmTNF-transgenic (tmTNF-tg) mice. tmTNF overexpression resulted in enlarged peripheral lymph nodes (PLNs) and spleen, accompanied by an increase in small splenic lymphoid follicles, with less well-defined primary B cell follicles and T cell zones. In tmTNF-tg mice, the spleen, but not PLNs, contained reduced germinal center (GC) B cell fractions, with low Ki67 expression and reduced dark zone characteristics. In line with this, smaller fractions of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells were observed with a decreased Tfh:Tfr ratio. Moreover, plasma cell (PC) formation in the spleen of tmTNF-tg mice decreased and skewed towards IgA and IgM expression. Genetic deletion of TNFRI or –II resulted in a normalization of follicle morphology in the spleen of tmTNF-tg mice, but GC B cell and PC fractions remained abnormal. These findings demonstrate that tightly regulated tmTNF is important for proper SLO development and function, and that aberrations induced by tmTNF overexpression are site-specific and mediated via TNFRI and/or TNFRII signaling.
Highlights
Secondary lymphoid organs (SLOs), including spleen and lymph nodes (LNs), are central sites for the initiation of adaptive immune responses
We show that transmembrane TNF (tmTNF) overexpression has clear effects on spleen morphology and splenic lymphoid follicle development
Overexpression of tmTNF resulted in an increased number of lymphoid follicles in the spleen, which were on average reduced in size
Summary
Secondary lymphoid organs (SLOs), including spleen and lymph nodes (LNs), are central sites for the initiation of adaptive immune responses To efficiently establish these responses, SLOs have a tightly organized architecture enabling efficient interactions between incoming (naive) immune cells and local antigens, presenting as immune and stromal cells [1]. We used an experimental mouse model (Tg86) that has enforced tmTNF expression in the presence of physiological sTNF levels due to introduction of a mutant TNF gene construct harboring a defect in the ADAM17 cleavage site (muTNF∆1–12 ). This generates an increase in tmTNF expression while retaining physiological sTNF levels [11,12]. We explored the contribution of TNFRI and –II signaling to the observed changes
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