Background/Purpose:

The NF-κB family of transcription factors plays a crucial role in chronic inflammatory diseases and can be activated via two distinct pathways. Non-canonical NF-κB signaling can be induced by different signals, including transmembrane ™TNF ligation to TNF receptor 2 (TNFR2), which is restricted to specific cell types including endothelial cells (EC). Activation of the non-canonical NF-κB pathway in EC is involved in differentiation into high endothelial venules (HEV), which are specialized lymphoid vessels that play an essential role in the recruitment of B and T lymphocytes into lymph nodes (LN), resulting in LN enlargement. tmTNF transgenic (tg) mice that overexpress tmTNF develop chronic inflammatory features, including arthritis and axial inflammation.

The objective of the current study was to investigate LN size and composition, including stromal cell and lymphocyte subsets in tmTNF tg mice. We hypothesized that overexpression of tmTNF results in increased non-canonical NF-κB signaling in HEV leading to enlarged LN due to enhanced migration of B and T lymphocytes into LNs.

Methods:

Peripheral LN (PLN) and mesenteric LN (MLN) of 7 week old tmTNF tg mice and age-matched wild type (WT) mice were collected and dissected and subsequently analyzed using flow cytometry. Cellular markers were used to distinguish between different (CD31+) EC subsets, including MECA79+ high endothelial cells, and B lymphocytes (CD19+) and T lymphocytes (CD3+).

Results:

Lymph nodes of tmTNF tg mice were macroscopically enlarged and had more than two-fold increased total cell numbers when compared to WT mice (tmTNF tg PLN: 23,7*10⁶±7,9*10⁶; MLN: 24,9*10⁶±5,3*10⁶ and WT PLN: 5,2*10⁶±1,0*10⁶; MLN: 10,4*10⁶±4,6*10⁶). The total number of high endothelial cells (HEC) in tmTNF tg mice LN was also increased when compared to WT (tmTNF tg PLN: 2,3*10³±0,50*10³; MLN: 1,9*10³±0,64*10² and WT PLN: 714±393; MLN: 1.199±506). In addition, the total amount of capillary endothelial cells (CEC) was increased in tmTNF tg mice (tmTNF tg PLN: 2067±42; MLN: 2425±71 and WT PLN: 1097±609; MLN: 1327±230). Notably, the ratio between HEC and CEC was also increased in the LN of tmTNF tg mice when compared to WT mice (tmTNF tg PLN: 1,10±0,241 and WT PLN: 0,66±0,006). In addition, total B lymphocyte and T lymphocyte numbers in LN of tmTNF tg mice were strongly increased compared to WT mice (B lymphocytes: tmTNFtg PLN: 10,2*10⁶±3,5*10⁶; MLN: 10,9*10⁶±1,8*10⁶ and WT PLN: 2,8*10⁶±5,8*10⁵; MLN; 5,8*10⁶±2,4*10⁶, T lymphocytes: tmTNFtg PLN: 12,8*10⁶±4,5*10⁶; MLN: 14,2*10⁶±2,8*10⁶ and WT PLN: 2,5*10⁶±3,8*10⁵; MLN: 4,7*10⁶±2,1*10⁶).

Conclusion:

Overexpression of tmTNF in mice leads to an increase in LN size which is accompanied by an increase in total HEC and CEC numbers and an increased HEC:CEC ratio. Also, and B and T lymphocyte numbers in PLN and MLN were increased. The increase of HEC may be the result of enhanced non-canonical NF-κB activation in EC, resulting in enhanced recruitment of B and T lymphocytes into LN. Consequently, interfering with non-canonical NF-κB signaling in EC may be a promising treatment strategy to dampen inflammation in immune-mediated inflammatory diseases, which is the subject of current studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transmembrane-tnf-tmtnf-transgenic-mice-exhibit-enlarged-lymph-nodes-and-elevated-numbers-of-high-endothelial-cells-associated-with-increased-lymphocyte-recruitment/