Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission

Abstract

An important aspect of clinical immunity to malaria is the ability to down-regulate inflammatory responses, once parasitaemia is under control, in order to avoid immunemediated pathology. The role of classical (CD4 CD127lo/À FOXP3 1 ) Treg in this process, however, remains controversial. Thus, we have characterized the frequency, phenotype and function of Treg populations, over time, in healthy individuals in The Gambia. We observed that both the percentage and the absolute number of CD4lo/À T cells were higher among individuals living in a rural village with highly seasonal malaria transmission than among individuals living in an urban area where malaria rarely occurs. These CD4 1 FOXP31 CD127 lo/À T cells exhibited an effector memory and apoptosis-prone phenotype and suppressed cytokine production in response to malaria antigen. Cells from individuals exposed to malaria expressed significantly higher levels of mRNA for forkhead box P3 and T-box 21 (T-BET) at the end of the malaria transmission season than at the end of the non-transmission season. Importantly, the ratio of T-BET to forkhead box P3 was remarkably consistent between populations and over time, indicating that in healthy individuals, a transient increase in Th1 responses during the malaria transmission season is balanced by a commensurate Treg response, ensuring that immune homeostasis is maintained.Key words: Human . Malaria . Regulation . T cells Supporting Information available online IntroductionA strong pro-inflammatory response, characterized by IFN-g and TNF-a, contributes to the initial killing and clearance of malariainfected RBC [1]. However, immune-mediated pathologypredominantly observed in non-immune and semi-immune subjects -has been linked to sustained and/or excessive inflammatory responses in animal malaria models [2] and human disease [3]. Indeed, ratios of inflammatory to regulatory cytokines seem to determine the severity of disease: low levels of and 8] have been associated with acute or severe malaria, and high ratios of IFN-g, TNF-a and IL-12 to TGF-b or IL-10 are associated with decreased risk of malaria infection but increased risk of clinical disease in those who do à These authors contributed equally to this work. 1288become infected [9,10]. Moreover, in vitro parasite-induced IFN-g production by PBMC is considerably lower among clinically immune individuals than among semi-immune subjects [11,12]. This has led to the hypothesis that the ability to down-regulate inflammatory responses -once parasitaemia is under control -is crucial to avoid immune-mediated pathology, and may therefore be an important feature of clinical immunity to malaria [3,13].The balance between pro-inflammatory and regulatory immune mechanisms is crucial in determining the outcome of many parasitic infections [13,14]: pro-inflammatory responses, though essential to clear infection, can also lead to severe disease and need to be very tightly regulated in order to maintain immune homeostasis.Treg, first characterised by a high level of CD25 expressi...

Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/–) ex vivo and after in vitro restimulation with malaria antigens

“…4) Although conventional memory T cells are regarded as long-lived cells [55,56], human Treg are thought to be short lived [42]; this has recently been linked to high levels of CD95 expression on human memory Treg [53]. We have observed transient expansion of FOXP3 1 Treg populations in a Gambian population exposed to seasonal malaria infection [38] suggesting that human Treg populations are highly dynamic. To determine whether activation-induced cell death by apoptosis might play a role in regulating Treg numbers, conventional T cells and FOXP3…”

“…As for conventional T cells, it has been shown that the majority of CD4 T cells with regard to the expression of CCR and apoptotic molecules and suggest that CD25, rather than being a marker of Treg per se, is a marker of activated Treg. Given our interest in Treg function during malaria infection [38,[44][45][46][47], we further aimed to study these markers in relation to Treg activation status in vitro, using Plasmodium falciparum schizont extract (PfSE). Importantly, we show that -irrespective of the culture conditions -the phenotype of FOXP3 1 T cells is modified when they are kept in in vitro culture, affecting both expression of CCR and molecules involved in apoptosis, indicating a need for caution when comparing data from in vitro and ex vivo studies.…”

“…Indeed, it is increasingly recognised that human Treg are far more heterogenous than murine Treg [9], and that even CD4 [37]. Functionally distinct Treg subpopulations have also been identified on the basis of forkhead box P3 (FOXP3) expression intensity and CD45RA expression [10].We have previously reported that in areas of seasonal malaria transmission, Treg may expand alongside effector memory (EM) T cells when malaria exposure is high, and that both populations may contract once exposure decreases [38]; this contraction may involve apoptotic pathways. Treg have been shown to be highly susceptible to spontaneous cell death or cytokine-deprivation induced death [39].…”

“…We have previously reported that in areas of seasonal malaria transmission, Treg may expand alongside effector memory (EM) T cells when malaria exposure is high, and that both populations may contract once exposure decreases [38]; this contraction may involve apoptotic pathways. Treg have been shown to be highly susceptible to spontaneous cell death or cytokine-deprivation induced death [39].…”

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

“…FTY720 also has been shown to affect regulatory T cells (Tregs) by increasing the expression of IL-10 and CTLA-4 in vitro (55), promoting Treg activity in vivo (56) and more recently by modulating the reciprocal differentiation of inducible Tregs and Th1 cells (57). The role of Tregs in malaria infection remains controversial (58), and therefore the impact of S1P on this cell type during infection requires further investigation. Despite FTY720 mainly affecting T cells (15), an effect on B and NK cells cannot be excluded (59).…”