Induction of Inhibitory Receptors on T Cells DuringPlasmodium vivaxMalaria Impairs Cytokine Production

Abstract

The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4(+) and CD8(+) T cells. Higher frequencies of CD4(+) express more than 1 regulatory molecule compared to CD8(+) T cells. Moreover, lower proportions of CD4(+) T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin-3 signaling restores the cytokine production by antigen-specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function.

Regulatory issues in immunity to liver and blood-stage malaria

“…Importantly, increased expression of both PD-1 and LAG-3 as a consequence of persistent Plasmodium falciparum infection has been confirmed in a cohort of Kenyan children [23]. Additionally, simultaneous blockade of CTLA-4, PD-1 and TIM-3 was shown to substantially improve the functionality of CD8 T cells, as measured by ex vivo cytokine production upon antigen stimulation [24]. Although it is possible that the lack of sterilizing protection upon natural exposure is due to functional exhaustion of CD8 T cells, further studies are required to clarify the biological mechanisms underlying these observations.…”

Acute Malaria Induces PD1+CTLA4+ Effector T Cells with Cell-Extrinsic Suppressor Function

“…falciparum , express higher levels of CTLA4 and PD1 on their T cells than uninfected or unexposed control subjects [24, 26–28]. This increased expression has been proposed to be a sign of T cell exhaustion.…”

“…Recent studies reported that CTLA4 and PD1 are also upregulated on the T cells of patients with acute malaria or children that are regularly exposed to P . falciparum in endemic areas [24, 26–28]. However, it remains unclear how the expression of these coinhibitory receptors influences the immune response to acute P .…”

Surface expression of inhibitory (CTLA-4) and stimulatory (OX40) receptors by CD4+ regulatory T cell subsets circulating in human malaria

“…In contrast, improved T cell responses to malaria parasites both ex-vivo and in vivo can be induced by the simultaneous blockade of CTLA-4 and other inhibitory receptors, e.g . lymphocyte activation gene-3 (LAG-3), programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3) [48–50]. Moreover, enhancing OX40 signaling with agonist antibodies improved effector T cell responses, antibody production, and parasite clearance in experimental murine malaria [36].…”