draining-lymph-node-metastasis-model-for-assessing-dynamics-antigen

Draining Lymph Node Metastasis Model for Assessing the Dynamics of Antigen-Specific CD8<sup>+</sup> T Cells During Tumorigenesis

Tumor antigen-specific CD8+ T cells from draining lymph nodes gain an accumulating importance in mounting anti-tumor immune response during tumorigenesis. ...

Third Military Medical University

Transmissible gastroenteritis (TGE) and porcine epidemic diarrhea (PED) are highly transmissible intestinal infections caused by transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV), respectively. They are clinically associated with vomiting, diarrhea, and dehydration in piglets. An imbalance in Na uptake by intestinal epithelial cells causes TGEV/PEDV-induced diarrhea. However, the mechanism by which TGEV/PEDV-infection in piglets causes Na imbalance diarrhea has not been elucidated. In the present study, we demonstrated that specific inhibition of NHE3 activity caused small intestinal bulging, intestinal wall thinning and severe diarrhea in piglets, consistent with the signs of TGEV/PEDV infection. This study further elucidated the role of NHE3 in TGEV/PEDV-induced diarrhea. In this study, small intestinal epithelial cells (IPEC-J2) were used as a model of infection. The results showed that TGEV/PEDV infection reduced NHE3 activity and Na uptake in IPEC-J2 cells. Further studies revealed that the use of NHE3-specific inhibitors could reduce the amount of cell membrane NHE3, thereby decreasing Na uptake and ultimately leading to diarrhea. Transcriptomic studies performed on obtained jejunal tissues were also consistent with pre-laboratory results. This study will provide a basis for understanding Na imbalance diarrhea caused by TGEV/PEDV, as well as for elucidating the diarrheal pathogenesis of other members of α-animal coronaviruses.

Decreased NHE3 activity in intestinal epithelial cells in TGEV and PEDV-induced piglet diarrhea.

Follicular regulatory T cells (Tfrs), a specialized subset of regulatory T cells (Tregs), have a particular role in the control of follicular helper T cell-driven germinal center (GC) responses. Following differentiation signals similar to those received by follicular helper T cells (Tfhs), Tfrs gain expression of characteristic chemokine receptors and transcription factors, such as CXCR5 and Bcl-6, allowing them to migrate into the B-cell follicle and perform in situ suppression. Thus, together with Tfhs, Tfrs help maintaining an optimized GC-reaction. However, the mechanism underlying the Treg-to-Tfr transition remains obscure. Here, we established a highly reproducible protocol for investigating the differentiation of Tregs into Tfrs by constructing spleen-chimeric mice combined with retrovirus transduction. We demonstrated that using this strategy, over 4 folds of Tregs could differentiate into Tfrs in Bcl-6 overexpression group compared to control counterparts (Migr1), and Bcl-6 could efficiently promote Tfr differentiation during acute viral infection. Hence, this method provides us an easy access to investigate the factors that regulate the differentiation program that converts Tregs into Tfrs, which will enhance our understanding of the networks regulating GC-reaction and shed new light on the molecular basis of immune homeostasis.

A novel strategy to investigate the factors regulating the Treg to Tfr transition during acute viral infection.

Cytotoxic CD8 T cells are the main focus of efforts to understand anti-tumor immunity and immunotherapy. The adoptive transfer of tumor-reactive cytotoxic CD8 T lymphocytes expanded and differentiated  has long been considered the primary strategy in adaptive anti-tumor immunity, however, the majority of the transferred tumor antigen-specific CD8 T cells differentiated into CD39CD69 exhausted progenies, limiting its effects in repressing tumor growth. Contrarily, less attention has been addressed to the role of CD4 T cells during tumorigenesis. Using a mouse model of metastatic melanoma, we found that transferring tumor-specific CD4 T cells into recipients induces substantial regression of the established metastatic tumors. Notably,  activated CD4 T cells developed into cytotoxic CD4 T cells  and get exhausted gradually. The blockade of PD-L1 signaling resulted in an expansion of tumor specific CD4 T cells, which could better control the established metastatic melanoma. Moreover, the tumor-specific memory CD4 T cell can prevent mice from tumor metastasis, and the tumor-specific effector CD4 T cells can also mitigate the established metastatic tumor. Overall, our findings suggest a novel mechanism of CD4 T cells in curtailing tumor metastasis and confirm their therapeutic role in combination with PD-L1 blockade in cancer immunotherapy. Hence, a better understanding of cytotoxic CD4 T cell-mediated tumor regression could provide an alternative choice for patients exhibiting suboptimal or no response to CD8 T cell-based immunotherapies.

Tumor-Specific CD4 T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4 T Cells.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8 T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8 T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8 T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8 cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (T) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-T cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-T cells could be harnessed to potentiate anti-tumor immunotherapy.

Article	Year
Decreased NHE3 activity in intestinal epithelial cells in TGEV and PEDV-induced piglet diarrhea. Veterinary microbiology\| PubMed ID: 34749283	2021
A novel strategy to investigate the factors regulating the Treg to Tfr transition during acute viral infection. Journal of immunological methods\| PubMed ID: 35398062	2022
Tumor-Specific CD4 T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4 T Cells. Frontiers in immunology\| PubMed ID: 35784297	2022
The primordial differentiation of tumor-specific memory CD8 T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell\| PubMed ID: 36208623	2022
Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 36859455	2023
Author Correction: Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 37225839	2023

Ling Ran

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