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.