Age-Related Differences in Naturally Acquired T Cell Memory to Plasmodium falciparum Merozoite Surface Protein 1

Abstract

Naturally acquired immunity to Plasmodium falciparum malaria in malaria holoendemic areas is characterized by the gradual, age-related development of protection against high-density parasitemia and clinical malaria. Animal studies, and less commonly, observations of humans with malaria, suggest that T-cell responses are important in the development and maintenance of this immunity, which is mediated primarily by antibodies that slow repeated cycles of merozoites through erythrocytes. To advance our rather limited knowledge on human T-cell immunity to blood stage malaria infection, we evaluated CD4 and CD8 T-cell effector memory subset responses to the 42 kDa C-terminal fragment of Merozoite Surface Protein 1 (MSP142), a malaria vaccine candidate, by 49 healthy 0.5 to ≥18 year old residents of a holoendemic area in western Kenya. The proportion of individuals with peripheral blood mononuclear cell MSP142 driven IFN-γ ELISPOT responses increased from 20% (2/20) among 0.5–1 year old children to 90% (9/10) of adults ≥18 years (P = 0.01); parallel increases in the magnitude of IFN-γ responses were observed across all age groups (0.5, 1, 2, 5 and ≥18 years, P = 0.001). Less than 1% of total CD4 and CD8 T-cells from both children and adults produced IFN-γ in response to MSP142. However, adults had higher proportions of MSP142 driven IFN-γ secreting CD4 and CD8 effector memory (CD45RA− CD62L−) T-cells than children (CD4: 50.9% vs. 28.8%, P = 0.036; CD8: 52.1% vs. 18.3%, respectively P = 0.009). In contrast, MSP142 driven IFN-γ secreting naïve-like, transitional (CD45RA+ CD62L+) CD4 and CD8 cells were the predominant T-cell subset among children with significantly fewer of these cells in adults (CD4: 34.9% vs. 5.1%, P = 0.002; CD8: 47.0% vs. 20.5%, respectively, P = 0.030). These data support the concept that meaningful age-related differences exist in the quality of T-cell immunity to malaria antigens such as MSP1.

Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8 + T-Cell Differentiation

“…In the individual depicted here, clear CD8 ϩ T-cell populations are observed for all specificities with the exception of YLL. (40,41). This is consistent with the recent description of stem cell-like memory T cells, which express many other surface markers typically associated with antigen-inexperienced naïve cells and likely represent a very early stage of memory T-cell differentiation (42).…”

Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

“…Less is known about the role of T cells in human malaria infections. Recently, age-related qualitative differences in the T cell response to merozoite surface protein 1 were shown, which may contribute to age-related malarial immunity (10). Further investigation in the role of T cells in protection from severe disease in humans is needed.…”

Chronic Plasmodium chabaudi Infection Generates CD4 Memory T Cells with Increased T Cell Receptor Sensitivity but Poor Secondary Expansion and Increased Apoptosis

“…lood-stage malaria infection, like other chronic infections, generates effector memory T cells (Tem) in mice and humans (1,2). Children living in areas with high malaria transmission demonstrate a decrease in the incidence of malaria disease as they grow older (3).…”

“…Children living in areas with high malaria transmission demonstrate a decrease in the incidence of malaria disease as they grow older (3). This decrease in malarial incidence is associated with an increased number of gamma interferon (IFN-␥)-producing effector/effector memory CD4 T cells upon parasite exposure (1,2). However, the levels of malaria-responsive T cells and malaria antigen-specific antibody titers decay over time (4)(5)(6), as does clinical immunity.…”