Phenotypic Evidence of T Cell Exhaustion and Senescence During Symptomatic Plasmodium falciparum Malaria

Abstract

T cells play significant roles during Plasmodium falciparum infections. Their regulation of the immune response in symptomatic children with malaria has been deemed necessary to prevent immune associated pathology. In this study, we phenotypically characterized the expression of T cell inhibitory(PD-1, CTLA-4) and senescent markers (CD28(-), CD57) from children with symptomatic malaria, asymptomatic malaria and healthy controls using flow cytometry. We observed increased expression of T cell exhaustion and senescence markers in the symptomatic children compared to the asymptomatic and healthy controls. T cell senescence markers were more highly expressed on CD8 T cells than on CD4 T cells. Asymptomatically infected children had comparable levels of these markers with healthy controls except for CD8+ PD-1+ T cells which were significantly elevated in the asymptomatic children. Also, using multivariate regression analysis, CTLA-4 was the only marker that could predict parasitaemia level. The results suggest that the upregulation of immune exhaustion and senescence markers during symptomatic malaria may affect the effector function of T cells leading to inefficient clearance of parasites, hence the inability to develop sterile immunity to malaria.

Comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections

“…Alternatively, abnormal cell death through apoptosis has also been indicated as another mechanism by which lymphocytes are depleted from blood during acute malaria infections [45]. This explanation is corroborated by the observation of high expression of exhaustion and senescence markers on T cells from children with symptomatic malaria compared to asymptomatic participants [46,47]. It is becoming increasingly clear that many chronic human infectious diseases, including P. falciparum infections [48,49] and HIV [50], are associated with the accumulation of atypical memory B cells that are characterized by the expression of exhausted markers, and a reduction of [51].…”

Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression

“…It has been shown that RA patients had a multi-reactive anti-herpes IgM profile, which was associated with disease activity [46]. Also, expansions of CD28-T cells have also been documented in various chronic infections, including malaria [47], HIV [48] and human T-lymphotropic virus type-I (HTLV-1) [49]. More studies are necessary to explore the role of persistent infections during clinical progression in RA.…”

Pathogenic Th1 responses in CHIKV‐induced inflammation and their modulation upon Plasmodium parasites co‐infection

“…This was supported by previous findings where apoptosis in lymph nodes and secondary lymphoid organs upon malaria infection was described. 133,134 In addition, it is also known that blood-stage malaria infections suppress dendritic cell (DC) responses by affecting DC maturation, [142][143][144] reducing surface expression of MHC-II 142,[145][146][147] and co-stimulatory molecule CD86, 146 inducing DC apoptosis 148,149 and impairing their ability to process and present parasite-derived antigens to T cells. 150,151 In line with this, reduced numbers of conventional DCs in the pLN of co-infected mice were also observed, suggesting that reduced expansion of CD4 + T cells might be due in part to the drop in DCs numbers associated with malaria.…”

“…119 Taken together, these results suggest that the expansion, survival, and trafficking of pathogenic CHIKV-specific CD4 + T cells in the pLN/footpad axis are hampered by co-infections with Plasmodium parasites (Figure 1). Additionally, the contribution of T cell anergy 139,140 and exhaustion [141][142][143][144] extensively reported upon severe malaria infections remain to be explored.…”