From helping to regulating – A transcriptomic profile of Ifng+ Il10+ Il21+ Cd4+ Th1 cells indicates their role in regulating inflammation during experimental trypanosomosis

Abstract

IntroductionTrypanosoma evansi parasite infections cause a chronic animal wasting disease called Surra, and cases of atypical Human Trypanosomosis (aHT). In experimental models, T. evansi infections are hallmarked by the early onset of excessive inflammation. Therefore, balancing the production of inflammatory cytokines by anti-inflammatory IL-10 is crucial for prolonged survival.MethodsTo improve the understanding of trypanosomosis induced immunopathology, we used scRNA-seq data from an experimental chronic T. evansi infection mouse model, resembling natural infection in terms of disease characteristics. Results and discussionFor the first time, obtained results allowed to assess the transcriptomic profile and heterogeneity of splenic CD4+ T cell subsets, during a trypanosome infection. Here, the predominant subpopulation of T cells was represented by Tbx21(T-bet)+Ccr5+ Id2+ type 1 helper T cells (Th1), followed by Icos+ Cxcr5+Follicular T helper cells (Tfh) and very minor fraction of Il2ra(CD25)+Foxp3+ regulatory T cells (Tregs). Interestingly, the profile of Th1 cells shows that besides Ifng, these cells express high levels of Il10 and Il21, coding for anti-inflammatory and immunoregulatory cytokines. This coincides with the elevated expression of key genes involved in IL-10 and IL-21 secretion pathway such as Stat1 and Stat3, as well as the transcriptional factors Prdm1 (Blimp 1), and Maf (c-Maf). In contrast, there is virtually no IL-10 transcription detected in the Treg population. Finally, differential gene expression and gene ontology analysis of infection-induced Ifng+ Il10+ Il21+ Th1 cells highlights their suppressive function on T cell activation, differentiation and INF-γ production itself. This indicates that during trypanosome infections, the Ifng+ Il10+ Il21+ Th1 cells, rather than Tregs, assume an immune regulatory role that is needed for dampening inflammation.

Advances in the Immunology of the Host–Parasite Interactions in African Trypanosomosis, including Single-Cell Transcriptomics

“…Interestingly, however, CD4 + T cells are also crucial producers of IL-10 at this stage, needed for the anti-inflammatory cytokine context alongside T. brucei -induced alternatively activated macrophages [ 95 ]. As it will be outlined in detail below, the most recent scRNA-seq data has provided new insights into the cellular source of both IFN-γ and IL-10, showing that a unique population of CD4 + T cells is capable of producing both ‘counteracting’ cytokines simultaneously [ 96 ].…”

“…As already indicated above, both CD4 + Th1 and Th2 cells are known to play distinct roles during trypanosome infections. Hence, having recent access to spleen scRNA-seq data has allowed to obtain a more detailed view of the transcriptome profile alterations that take place during infection [ 96 ]. Comparative data analysis of naïve C57BL/6 splenocytes and cells derived from 14- and 42 days post infection allowed to characterize six CD4 + T cell subpopulations affected by experimental T.…”

“…This suggests that the T cell biology of trypanosomosis should be re-addressed with a focus on Th1 cells, the plastic immune regulatory role of these cells, and their contribution to the regulation of survival of the host. Indeed, from this recent data, it appears that these cells are crucial during the early stage of infection by aiding macrophage activation and parasite clearance, while later on in infection, they are partially involved in alleviating cellular activation and ultimately reducing inflammation-induced pathology during infection [ 96 ].…”

“…In turn, this leads to the abrogation of germinal center formation. Hence, this finding suggests that trypanosomes have developed an additional mechanism to evade antibody-mediated immune attacks by depriving the host of the capacity to generate high-affinity anti-parasite antibodies [ 96 ].…”

Recent Progress in the Detection of Surra, a Neglected Disease Caused by Trypanosoma evansi with a One Health Impact in Large Parts of the Tropic and Sub-Tropic World

“…The host immunoglobulin response also becomes helpless since trypanosomes can inhibit complement-mediated lysis by removing bound immunoglobulins from their surface [ 24 , 25 , 26 , 27 , 28 ]. On top of that, the disruption of the host B cell compartment by T. evansi further increases the difficulty in combatting these parasites [ 29 , 30 , 31 , 32 , 33 ].…”