Heterogeneous and Tissue-Specific Regulation of Effector T Cell Responses by IFN-γ during Plasmodium berghei ANKA Infection

Abstract

IFN-γ and T cells are both required for the development of experimental cerebral malaria during P. berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4+ and CD8+ T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN- γ−/− mice during P. berghei ANKA infection. The expansion of splenic CD4+ and CD8+ T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN- γ−/− mice, however, the migration to, and accumulation of, effector CD4+ and CD8+ T cells in the lung, liver and brain was altered in IFN- γ−/− mice. Interestingly, activation and accumulation of T cells in various non-lymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN- γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended upon active IFN- γ-dependent environmental signals – leading to T cell apoptosis - rather than upon intrinsic alterations in T cell programming. This is the first study to fully investigate the role of IFN- γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells.

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

“…1B). These data suggest that the IL-12 and IFN-γ responses to blood-stage malaria are involved in promoting CD4 T-cell contraction and support a recent report that CD4 T-cell contraction is reduced in P. berghei-infected IFN-γ −/− mice (16).…”

“…In viral infections, elevated expression of IL-12 favors the development of responding T cells into short-lived, terminal effector cells rather than memory precursor effector cells (11,15); however less is known about the effects of inflammatory cytokines on the development of memory T cells during Plasmodium infections. There is evidence that during blood-stage Plasmodium infection IFN-γ is detrimental to the survival of Plasmodium-specific CD4 T cells by regulating its contraction phase (12,16). The observation that concurrent infection with Plasmodium falciparum impairs the development of vaccine-induced Plasmodium antigen-specific memory CD4 T cells (17) further suggests that the formation of T-cell-mediated immunological memory is impaired during malaria.…”

“…Upon infection, the cytokines IL-12 and IFN-γ promote the differentiation of naive CD4 T cells into Th1 cells, which are known to mediate antibody-independent protection against Plasmodium infection (3). IL-12 and IFN-γ can further influence CD4 T-cell fate (19,20), and malaria-induced IFN-γ has been implicated in regulating the contraction of Plasmodium-specific CD4 T cells (12,16). Although the effects of IL-12 and IFN-γ on T-cell development and survival are well characterized in many infection models (11,15,21,22), they have not been investigated thoroughly during malaria.…”

“…S1A), a finding that is consistent with reports from other murine Plasmodium blood-stage infection models (23,24). The peak of the inflammatory response to PbA infection of BALB/c mice occurs around days 4 and 5 post infection (25), and this acute phase of the response is followed by contraction of responding CD4 T cells starting around day 7 post infection (16).…”

Apoptotic Programs Are Determined during Lineage Commitment of CD4+ T Effectors: Selective Regulation of T Effector-Memory Apoptosis by Inducible Nitric Oxide Synthase

“…Whereas IFN-g regulates T cell number in many Ag-based systems, these studies have not always addressed whether these outcomes result from its effects on T cell differentiation, on APCs, or other immune cells, and are in some instances confounded by its effect on T cell proliferation (23,(34)(35)(36)(37). Indeed, the deficiency of IFN-g also compromises AICD (38), a pathway by which activated T cells generated in response to high concentrations of Ag or in situations of chronic infection or autoreactive cells are deleted (9).…”