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

Abstract

In acute Plasmodium falciparum (P. falciparum) malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4+ T cell functions in malaria, blood samples were obtained from patients with acute P. falciparum malaria treated in Germany. Flow cytometric analysis showed a more frequent expression of CTLA4 and PD1 on CD4+ T cells of malaria patients than of healthy control subjects. In vitro stimulation with P. falciparum-infected red blood cells revealed a distinct population of PD1+CTLA4+CD4+ T cells that simultaneously produced IFNγ and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1+CTLA4+CD4+ T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1+CTLA4+CD4+ T cells suppressed the proliferation of the total CD4+ population in response to anti-CD3/28 and plasmodial antigens in a cell-extrinsic manner. The response to other specific antigens was not suppressed. Thus, acute P. falciparum malaria induces P. falciparum-specific PD1+CTLA4+CD4+ Teffector cells that coproduce IFNγ and IL10, and inhibit other CD4+ T cells. Transient induction of regulatory Teffector cells may be an important mechanism that controls T cell responses and might prevent severe inflammation in patients with malaria and potentially other acute infections.

Submicroscopic Plasmodium infection during pregnancy is associated with reduced antibody levels to tetanus toxoid

“…It would be interesting to investigate if this was due to a low amount of activated T lymphocytes. Other studies of the immune response to P. falciparum acute infections in humans and to P. berghei ANKA infections in mice reported increases in CTLA‐4 expression in activated T lymphocytes. In mononuclear cells isolated from cord blood of women with P. falciparum placental malaria, an increase in antigen‐specific CD4 + regulatory cells CD4 + CD25 + CTLA‐4 + with suppressive characteristics was observed .…”

Characterisation of anti-parasitic CD4+ T cell responses during malaria

“…We also showed that infection resolution induced marked changes in the CD4 + T cell transcriptome which is characterised by an immune regulatory signature. This confirms findings from cellular and molecular studies in the field showing the induction of regulatory molecules in CD4 + T cells during malaria 251,258 . It further suggests that not just one or two, but a whole suite of regulatory markers are induced early in infection, identifying an opportunity to intervene at an earlier timer point to protect against immune suppression.…”

“…IL-10 is important for limiting immune pathology caused by proinflammatory, anti-parasitic immune responses 37 . Tr1 cells are a major source of this cytokine in parasitic infections 37,42,155 , and PD1, CTLA4, TIM3, and LAG3 are also known to regulate antigen-specific T cell responses and can be markers of cellular exhaustion in infectious diseases, including malaria 233,239,[250][251][252] . We also observed increased expression of several genes associated with cytolytic activities after drug treatment, including granzymes A, B, H and K, and perforin, as has previously been reported for a subset of cytolytic CD38 + CD4 + T cells in CHMI studies that were positively associated with increased control of parasite growth 253 .…”

“…Blockade of several immune checkpoint molecules, as well as IL-10, has previously been shown to improve anti-parasitic T cell responses 233,239,[250][251][252] . We found that blocking PD1 at pre-treatment, when blood parasitemia was sub-microscopic, enhanced antigen-specific…”

“…However, Tr1 cell-specific expression of this molecule hasn't been confirmed in other systems. Tr1 cells have also been shown to have increased expression of CD226, CTLA-4, HLA-DR and IL-2/-15RB which are predominantly important for Tr1 mediated cell functions 251,254,321 .…”