CD4+IL9+ (Th9) cells as the major source of IL-9, potentially modulate Th17/Treg mediated host immune response during experimental cerebral malaria

Malaria is the deadliest vector-borne endoparasitic disease caused by different species of Plasmodium which resides into host red blood corpuscles (RBC) and induces severe inflammatory immune responses. According to World Health Organization globally 241 million malaria cases have been reported in 2020 along with 12% increased malaria deaths than the previous year. India accounted for about 82% of all malaria deaths in the South-East Asia Region (World malaria report, 2021). Most of the deaths by malaria infection are caused by lethal parasite Plasmodium falciparum which has a murine homolog known as Plasmodium berghei ANKA (PbA) (Craig et al., 2012). PbA results in almost 100% lethality in mice model of experimental cerebral malaria (ECM) within two weeks post infection due to severe anaemia, neurological damages, paralysis and coma (De Niz and Heussler, 2018; Keswani and Bhattacharyya, 2014) whereas Plasmodium yoelii cause nonlethal malaria in C57BL/6 and Swiss albino mice (Wykes and Good, 2009).

Host immune response is one of major factors which contribute to pathogenicity of malaria infection. Till now, it has been proved that the fine balance between pro-inflammatory and regulatory host immune responses determines the outcome of malaria infections. This equilibrium is maintained by different cytokines, chemokine, several immune cells viz. dendritic cells, macrophages, different subsets T cells. Although cytokines produced in response to malaria infection play important roles in the development of protective immunity, some of these cytokines also contribute to severe pathogenesis (Keswani and Bhattacharyya, 2014). Proinflammatory cytokines that are produced during the early phase of blood stage infection, including TNF-α, IL-12, and IFN-γ, are important for the development of Th1 responses and antiparasitic cellular immunity. However, excessive and persistent proinflammatory responses contribute significantly to the severity of lethal pathologies. In contrast, anti-inflammatory cytokines, such as IL-10, suppress proinflammatory cytokine and Th1 responses, thereby reducing the risk of developing severe pathology (Wu et al., 2021).

Beside other immune cells, CD4+ T-cells have been shown to play a critical role in immune-control of infection with Plasmodium parasites. The plasticity of CD4+ T cells is critical to the induction of immune response in a context-dependent manner, which reflects the complexity of the connection among different CD4+T cell subgroups. Exactly one decade back, a new subset of CD4+ T cells, which predominantly secrete the pleiotropic cytokine IL-9 was identified and christened as Th9 cells (Neurath and Kaplan, 2017). IL-9 has long been thought to be a Th2 cytokine, as it promotes allergic inflammation and is associated with various Th2 responses (Hauber et al., 2004). Th9 cells are differentiated from naïve CD4+ T cells mainly in presence of interleukin-4 (IL-4) and transforming growth factor beta (TGF-β) and are defined by their production of pleotropic cytokine IL-9 along with some amount of IL-10 and transcription factors like PU.1, IRF4, STAT6, STAT5, BATF etc. although these factors are not unique to Th9 cells (Kaplan, 2017). Previously it has been reported that Th9 cells are a discrete Th cell subset distinct from Th1, Th2, Th17, and regulatory T (Treg) cells. Accordingly, Th9 cells do not express subset-determining transcription factors like T-bet (Th1), GATA-3 (Th2), RORγT (Th17), or FoxP3 (Treg cells) at levels comparable to the respective T cell subsets, indicating that Th9 cells are an autonomous Th cell subset (Dardalhon et al., 2008; Veldhoen et al., 2008).

Th9 cells have critical roles in various infectious and parasitic diseases along with cancer (Végran et al., 2015; Cui et al., 2018). It provides immunity against helminth parasites. Moreover, they also play a vital role in vivo by providing anti-tumor immunity by secreting cytokines such as IL-9, IL-3, and IL-21 (He et al., 2020; Zheng and Lu, 2020). Interestingly, Th9 cells are also known to induce inflammation and thereby exacerbate inflammatory diseases, including allergic asthma, multiple sclerosis, rheumatoid arthritis, colitis model and inflammatory bowel disease (IBD) among others (Vyas and Goswami, 2018). However, the prominent role of IL-9 still remains a mystery due to its multifunctional nature.

Many of the CD4+ T-cells activated in a Plasmodium infection may undergo interconversion between defined cell subsets such as Treg and Th17 depending on antigen dose, APC, location, and cytokine/ chemokine environment (Kimura and Kishimoto, 2010; Perez-Mazliah and Langhorne, 2015; Sarkar et al., 2017). The capacity to identify and manipulate these possible mechanisms of CD4+ T-cell plasticity during Plasmodium infections would be of great value. However, the probable role of Th9 response and IL-9 are not yet explored in depth, which might play critical roles in the outcome of the infection. Therefore, the aim of this study was a detailed delineation of the status of IL-9 secreting Th9 cells in malaria infection and how Th9 cells modulate the activation of effector cells such as the Th17-Treg balance in response to Plasmodium infection is critical to design immunotherapeutic strategies against malaria parasite. To the best of our knowledge, the present study was the first one investigating the role of Th9 cells in ECM.

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