T follicular regulatory cells suppress Tfh-mediated B cell help and synergistically increase IL-10-producing B cells in breast carcinoma. Song Hongsheng,Liu Anzhou,Liu Guoxing,Wu Fang,Li Zhitao Immunologic research T follicular regulatory (Tfr) cell is a recently discovered subset of T regulatory (Treg) cells. The main function of Tfr cells is thought to suppress germinal cancer reaction and inhibit B cell proliferation and Ig production. However, recent studies demonstrate that Tfr cells may be required for high-affinity Ig formation during acute virus infections. The role of Tfr cells in breast cancer is not thoroughly investigated. In this study, total circulating CD4 T cells were sorted into CD25CXCR5 Treg-like, CD25CXCR5 Tfr-like, and CD25CXCR5 Tfh-like subsets. Data showed that the Tfr-like subset presented intermediate levels of both Foxp3 and Bcl-6, while the Treg-like subset was high in Foxp3 and low in Bcl-6, and the Tfh-like was high in Bcl-6 and low in Foxp3. Of note, the frequencies of Tfr-like and Treg-like cells were significantly elevated in breast cancer (BC) patients than in non-cancer (NC) controls. Tfr-like cells in BC patients also expressed significantly higher levels of Foxp3 than those in NC controls. Neither Treg-like nor Tfr-like cells could support Ig production from naive B cells, while Tfh-like cells potently supported Ig production from naive B cells. Tfr-like cells increased the availability of IL-10, both by directly producing IL-10 and by increasing IL-10 production from B cells. Interestingly, Tfr-like cells increased IL-10 production from B cells synergistically with Tfh cells, but at the same time, significantly reduced Ig production in the Tfh-B cell coculture. These Tfr-mediated effects on Tfh cells were not found in canonical Treg cells. Overall, this study demonstrates several distinctive features in circulating Tfr cells and suggests that Tfr cells may promote the formation of IL-10-producing B cells in BC. 10.1007/s12026-019-09090-y

Increased numbers of CD5+CD19+CD1dhighIL-10+ Bregs, CD4+Foxp3+ Tregs, CD4+CXCR5+Foxp3+ follicular regulatory T (TFR) cells in CHB or CHC patients. Wang Li,Qiu Jinpeng,Yu Lei,Hu Xiaoli,Zhao Pingwei,Jiang Yanfang Journal of translational medicine BACKGROUND:IL-10+ regulatory B (Bregs), CD4+Foxp3+ regulatory T (Tregs), and CD4+CXCR5+Foxp3+ follicular regulatory T (TFR) cells regulate the progression of infection disease. This study aimed at examining how those cells associated with the development of chronic hepatitis B (CHB) and chronic hepatitis C (CHC) in a Chinese population. METHODS:The numbers of circulating IL-10+ Bregs, Tregs and TFR cells in 31 CHC, 58 CHB patients and 22 healthy controls (HC) were examined by flow cytometry. The potential association of those cells with clinical measures was analyzed. RESULTS:The numbers of CD5+CD19+CD1dhighIL-10+ Bregs, Tregs and TFR cells and the levels of serum IL-10, IFN-γ and IL-2 in the CHB, and IL-10 and IFN-γ in the CHC patients were significantly higher than that in the HC (p<0.05). Furthermore, the numbers of circulating IL-10+ Bregs and the levels of serum IL-10, but not other cytokines tested were positively correlated with the levels of serum HBV DNA and ALT in the HBeAg- CHB patients as well as HCV RNA and ALT in CHC patients. Additionally, the numbers of circulating TFR cells were positively correlated with the levels of serum HBV DNA and ALT in the CHB patients as well as HCV RNA and ALT in the CHC patients. CONCLUSIONS:Increased numbers of circulating IL-10+ Bregs and TFR cells are associated with poor virus eradication and liver injury in CHB and CHC patients. Furthermore, the levels of serum IL-10 is associated with the hepatic flares. 10.1186/s12967-014-0251-9

Sirolimus therapy restores the PD-1+ICOS+Tfh:CD45RA-Foxp3 activated Tfr cell balance in primary Sjögren's syndrome. Molecular immunology BACKGROUND:Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. The current study was performed to investigate the roles of follicular helper T (Tfh) and follicular regulatory T (Tfr) subsets in patients with pSS, and to evaluate the effects of sirolimus on these cells. METHODS:Levels of circulating Tfh and Tfr subsets in 58 pSS patients and 26 healthy controls (HC) were determined by flow cytometry. These T cell subsets were also analyzed in 12 patients before and after treatment with sirolimus. Clinical features and correlations with follicular T cells were analyzed systematically. The discriminative ability of the cells and ratios was evaluated based on the area under the receiver operating characteristic curves. RESULTS:Patients with pSS had higher percentage and absolute number of PD-1+ICOS+Tfh cells, while lower percentage and absolute number of Tfr, activated regulatory T (aTreg) cells, and CD45RA-Foxp3 activated Tfr cells. Furthermore, increased number of PD-1+ICOS+Tfh cells was associated with B cells, while decreased numbers of Tfr and their subsets was strongly associated with aTreg cells in pSS patients. Also, the higher proportion of PD-1+ICOS+Tfh cells was positively correlated with higher level of autoantibodies, ESR, IgG, cytokines (IL-2, IL-4, IL-10, IL-17, IFN-γ, TNF-α, IL-21 and sIL-2αR), and disease activity. Unexpectedly, the elevated PD-1+ICOS+Tfh:CD45RA-Foxp3 activated Tfr ratio had the greatest ability to discriminate between pSS and HC, and sirolimus therapy restored the PD-1+ICOS+Tfh cells:CD45RA-Foxp3 activated Tfr ratio, and controlled disease activity. CONCLUSION:The novel ratio of PD-1+ICOS+Tfh to CD45RA-Foxp3 activated Tfr cells can effectively discriminate the pSS patients from controls, and Tfr cell subsets may resemble Treg cell lineages. Furthermore, the PD-1+ICOS+Tfh cells can be used as a biomarker of disease activity and to verify the therapeutic effects of sirolimus in pSS. 10.1016/j.molimm.2022.04.006