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Review
. 2023 Aug 28;13(1):156.
doi: 10.1186/s13578-023-01110-7.

Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes

Fei Sun #  1   2 , Chun-Liang Yang #  2 , Fa-Xi Wang  2 , Shan-Jie Rong  2 , Jia-Hui Luo  2 , Wan-Ying Lu  2 , Tian-Tian Yue  3 , Cong-Yi Wang  4   5 , Shi-Wei Liu  6
Affiliations
Review

Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes

Fei Sun et al. Cell Biosci. .

Abstract

Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained β cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory β cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy.

Keywords: PLN remodeling; Pancreatic draining lymph nodes (PLNs); Signal inputs; Signal outputs; Type 1 diabetes (T1D).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Pancreatic draining lymph nodes (PLNs) integrate signal inputs from various sources and undergo substantial immune remodeling to elicit anti-islet response. Pancreas derived autoantigens (soluble or presented by APCs), viral infections, gut microbiota components and circulating lymphocytes get access into PLNs, leading to and/or boosting the imbalance of Treg/Teff. The primed autoreactive T cells then serve as the major PLN outputs that infiltrate the pancreas and are responsible for T1D initiation. APC antigen-presenting cell, Treg regulatory T cell, Teff effector T cell
Fig. 2
Fig. 2
Breakdown of self-tolerance mechanism underpins T1D etiology. Briefly, self-tolerance is achieved at two different but related levels. Within the thymus, AIRE promotes the ectopic expression of tissue-specific antigens (TSAs) in thymic epithelial cells (TECs) and together with the presence of thymus resident DC, central tolerance is established through depleting autoreactive T cells (negative selection) and the induction of antigen-specific Treg cells. In parallel, within PLN, DEAF1 drives the ectopic expression of peripheral tissue antigens (PTAs) in lymph node stromal cells (LNSCs)/fibroblastic reticular cells (FRCs) and together with DAP12hi DCs, peripheral tolerance is established to further solidify immune homeostasis. Abnormalities in organismal tolerizing mechanism is thus fundamental to the pathogenesis of autoimmune disorders including T1D. Tol-DC tolerogenic dendritic cell, Act-DC activated dendritic cell, DAP12 DNAX-activating protein of 12 kDa, DEAF1 deformed epidermal autoregulatory factor 1
Fig. 3
Fig. 3
Pancreatic draining lymph nodes (PLNs) orchestrate and perpetuate the vicious cycle of islet-specific autoimmune reaction. Effector T cells (Teff) are efficient in β cell killing and are organized into specialized tertiary lymphoid organs (TLOs) with chronic T1D progression. Autoantibodies (Igs) produced by plasmocytes act as the early immune biomarker of T1D initiation and the autoantigens generated from dead islet β cells are presented by antigen presenting cells (APCs) to prime autoreactive T cells in PLNs. A minor population of autoreactive T cells are present in the form of stem like memory T cells (Tmem) to continuously fuel anti-islet immunity, considering that Teff have a short lifespan and would not persist once arriving at the islet niche
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