Search

Malaria remains a significant global public health problem. T follicular helper (Tfh) cells, a subset of CD4 + T cells, have the capacity to regulate B cells, plasma cells, and antibody production, among other functions. Myeloid-derived suppressor cells (MDSCs) possess strong immunosuppressive abilities and can negatively regulate various immune responses. However, the role of MDSCs in inhibiting Tfh-cell responses during Plasmodium infection remains unclear. In this study, we investigated the regulatory effect of MDSCs on Tfh cell-mediated immune responses upon Plasmodium infection. We found that the numbers of MDSCs increased upon Plasmodium infection. Further mechanism study revealed that MDSC-derived Arg-1 and PD-L1 prevented Tfh cell proliferation and activation. Conversely, the addition of nor-NOHA or anti-PD-L1 monoclonal antibodies enhanced the proliferation and activation of Tfh cells, indicating that the inhibitory effect of MDSCs on Tfh cells was dependent on Arg-1 and PD-1/PD-L1. In vivo depletion of MDSCs enhanced Tfh-cell responses and antibody production, as well as relieved symptoms of infected mice and improved their survival rates. These findings provide insights into the immunosuppressive role of MDSCs in inhibiting Tfh cell immune responses and further impairing humoral immunity. Our study provides new strategies for malaria prevention and control., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Interferon regulatory factor 4 (IRF4) is a crucial member of the IRF family of transcription factors and is pivotal in orchestrating the body's defense against tumors and infections by modulating the differentiation and functionality of immune cells. The role of IRF4 in mice during Schistosoma japonicum infection, as well as the effects of IRF4 deficiency on myeloid-derived suppressor cells (MDSCs), remains inadequately understood., Methods: Hematoxylin and eosin staining was used to evaluate the pathological damage in different organs of mice following infection with S. japonicum. Flow cytometry was employed to study the effect of IRF4 on the proliferation and function of myeloid-derived suppressor cells (MDSCs) in S. japonicum-infected mice., Results: Knockout of IRF4 in myeloid cells significantly mitigated pathological damage to the liver and lungs in mice infected with S. japonicum. Knockout of IRF4 in myeloid cells also inhibited the expansion and functionality of MDSCs by downregulating programmed death ligand 2 (PD-L2) expression and interleukin-1 alpha (IL-1α) secretion in mice infected with S. japonicum. Mechanistic studies revealed that IRF4 deficiency inhibited the expansion and function of MDSCs and that this inhibition was mediated by the STAT3 and AKT signaling pathways. Also, IRF4 myeloid knockout promoted the expansion of T cells in S. japonicum-infected mice, but had no significant effect on B cell aggregation., Conclusions: Overall, these findings highlight the importance of IRF4 in regulating MDSCs and their impact on tissue damage during S. japonicum infection, providing valuable insights into potential therapeutic targets for managing the pathological consequences of this parasitic infection., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments in this study are in accordance with the Chinese National Institute of Health Guide for the Care and Use of Laboratory Animals and have been approved by the Laboratory Animal Use and Care Committee of Guangzhou Medical University. The license number of strict enforcement is S2022-246. Consent for publication: All authors unanimously consent to the submission of the manuscript for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii-infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti-Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii-infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria., (Copyright © 2024 by The American Association of Immunologists, Inc.)