CD4 T-Cell Subsets in Malaria: TH1/TH2 Revisited

Abstract

CD4+ T-cells have been shown to play a central role in immune control of infection with Plasmodium parasites. At the erythrocytic stage of infection, IFN-γ production by CD4+ T-cells and CD4+ T-cell help for the B-cell response are required for control and elimination of infected red blood cells. CD4+ T-cells are also important for controlling Plasmodium pre-erythrocytic stages through the activation of parasite-specific CD8+ T-cells. However, excessive inflammatory responses triggered by the infection have been shown to drive pathology. Early classical experiments demonstrated a biphasic CD4+ T-cell response against erythrocytic stages in mice, in which T helper (Th)1 and antibody-helper CD4+ T-cells appear sequentially during a primary infection. While IFN-γ-producing Th1 cells do play a role in controlling acute infections, and they contribute to acute erythrocytic-stage pathology, it became apparent that a classical Th2 response producing IL-4 is not a critical feature of the CD4+ T-cell response during the chronic phase of infection. Rather, effective CD4+ T-cell help for B-cells, which can occur in the absence of IL-4, is required to control chronic parasitemia. IL-10, important to counterbalance inflammation and associated with protection from inflammatory-mediated severe malaria in both humans and experimental models, was originally considered be produced by CD4+ Th2 cells during infection. We review the interpretations of CD4+ T-cell responses during Plasmodium infection, proposed under the original Th1/Th2 paradigm, in light of more recent advances, including the identification of multifunctional T-cells such as Th1 cells co-expressing IFN-γ and IL-10, the identification of follicular helper T-cells (Tfh) as the predominant CD4+ T helper subset for B-cells, and the recognition of inherent plasticity in the fates of different CD4+ T-cells.

Regulatory issues in immunity to liver and blood-stage malaria

“…For instance, the CD4 T cell response in mouse malaria is biphasic. The naturally chronic P. chabaudi infection generates protracted peaks and dips [32] compared to the relatively quicker, yet similar pattern seen with P. yoelii (17XNL) infection [57]. Treg cell kinetics in malaria also shows a defined peak during the course of the infection in humans [30] and mice [58].…”

“…Unlike CD8 T cells that are more critical to the control of liver stage infection, the CD4 T cell-Bcell partnership and humoral immunity are vital to the control of blood stage malaria in humans and mice [32,33]. Helper T cells collaborate with B cells in germinal centers and shape humoral immune responses, which provide short-term control or long-term protection from reinfections (in mice) or clinical disease (humans) [34 ].…”

“…The Th1 subset of CD4 T cells, by virtue of their IFNg and IL-10 production, help control blood stage of malaria in humans and rodents [35 ,36]. Likewise, the Th2 subset aids in generating optimal antibody responses against plasmodium infections in humans and mice [32,37,38]. Th17 [39,40], Th22 [41], Tr27 [42], Tregs [43,44 ] and Tfh [45] have all been implicated in control of blood stage malaria.…”

Immune responses against protozoan parasites: a focus on the emerging role of Nod-like receptors

“…CD8 + T cells are important for controlling and killing Plasmodium at the liver stage [114–117], whereas CD4 + T cells are important at both the liver and blood stages [118–121]. CD4 + T cells assist CD8 + T cells in mounting an efficient immune response against Plasmodium parasites [122,123].…”

Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4

“…CD4 T helper (Th) cells are vital to the control of malaria in humans and the rodent models of disease 6 . Frequencies of activated Th cells increased during the course of malaria in mice and humans (Supplementary figures 1C, 2) and their depletion after established infection resulted in uncontrolled parasitemia and death in mice infected with the normally non-lethal rodent parasite, Plasmodium yoelii 17XNL ( Py ) (Supplementary figure 1A,B).…”