Distinct Contributions of CD4⁺and CD8⁺T Cells to Pathogenesis of Trypanosoma brucei Infection in the Context of Gamma Interferon and Interleukin-10

Abstract

T rypanosoma brucei species are protozoan parasites that cause severe disease and death to humans and animals in Africa (1-4). The parasites have developed highly sophisticated mechanisms to escape host immune responses, including antigenic variation of the variant surface glycoprotein (VSG) (3, 5), immunosuppression (4, 6, 7), and splenic B cell depletion (8, 9). For practical and ethical reasons, mouse models have become an alternative and have proven to be a cornerstone for studying African trypanosomiasis of humans and domestic animals (2). BALB/c mice are highly susceptible to T. brucei and Trypanosoma congolense infections, whereas C57BL/6 mice are relatively resistant, as measured by levels of parasitemia, immunosuppression, and survival time (10-12). Immunological experiments are often performed using C57BL/6 mice, because most of the gene-deficient mice available have the C57BL/6 background.Early studies showed that clearance of the parasites takes place mainly in the liver (13,14). Further studies demonstrated that the parasites are cleared by Kupffer cells via phagocytosis (15), which is mediated by IgM as well as IgG antibodies (Abs) specific for VSG (16,17). More recently, using IgM-deficient and B cell-deficient mice, it has been shown that IgG, but not IgM, Abs play a dominant role in the clearance of the parasites (18,19). Gamma interferon (IFN-␥), produced by VSG-specific T cell receptor ␣␤-positive (TCR␣␤ ϩ ) CD4 ϩ T cells (20), is critical for host resistance to African trypanosomes (18,(21)(22)(23)(24). It is likely that IFN-␥ exerts its protective effect through macrophage activation, resulting in secretion of tumor necrosis factor alpha (TNF-␣) and nitric oxide, which mediate parasite lysis or death (18,(25)(26)(27). However, overactivation of macrophages driven by excessive production of IFN-␥, particularly in the absence of interleukin-10 (IL-10) signaling, induces liver pathology, which kills the infected mice (15,28,29). As a regulatory cytokine, IL-10 is required to downregulate macrophage activation (15,23,28). Thus, IFN-␥ and IL-10 play crucial roles in protective as well as pathological immune responses during African trypanosomiasis (1, 4). CD4 ϩ and CD8 ϩ T cells are the major potential producers of IFN-␥ and IL-10. Although the important roles of IFN-␥ and IL-10 in the pathogenesis of African trypanosomiasis have been documented, the roles of CD4 ϩ and CD8 ϩ T cells in the development of the disease are not fully understood. In this study, we evaluated the contributions of CD4 ϩ and CD8 ϩ T cells to the pathogenesis of this disease. In particular, we focused on how their contributions were related to IFN-␥ and IL-10. MATERIALS AND METHODSMice. Female 8-to 10-week-old BALB/c AnNCrlBR (BALB/c) mice and 5-to 6-week-old female outbred Swiss white mice (CD1) were purchased from the National Cancer Institute (Frederick, MD). CD4Ϫ/Ϫ and

IL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ

“…Subsequent studies demonstrated that VSG-specific CD4 + T cells mediated protection via secretion of IFN-γ [ 13 , 55 ]; and splenic DCs were the primary cells responsible for activating naïve VSG-specific CD4 + T cell responses [ 16 , 17 ]. The protective role of CD4 + T cells and IFN-γ in African trypanosomiasis has been recently confirmed by independent groups [ 14 , 15 , 19 ]. In support of previous findings, we showed that either depletion of CD4 + T cells or neutralization of IFN-γ resulted in a significantly elevated peak parasitemia level in IL-27R -/- mice infected with T .…”

Interferon Gamma in African Trypanosome Infections: Friends or Foes?

“…These data suggest that CD8 + T cells kill mice via their secretions of IFN-γ during T. brucei brucei infections. The detrimental role of CD8 + T cells has been recently confirmed in BALB/c mice, as CD8 −/− mice in BALB/c background also survived significantly longer than the wild-type cohorts following infection with T. brucei brucei 10-26 ( 23 ). Surprisingly, IFN-γ production was completely abrogated in CD4 −/− , but not CD8 −/− BALB/c mice infected with T. brucei brucei 10-26 based on measurement of IFN-γ in plasma and spleen cell cultures, suggesting that IFN-γ is produced mainly by CD4 + T cells, but not CD8 + T cells in BALB/c mice infected with T. brucei brucei 10-26 ( 23 ), which is consistent to the observation in mice infected with T. congolense ( 16 , 22 ).…”

“…This notion was supported by an experiment performed using BALB/c mice infected with T. congolense ( 22 ). As CD4 + T cells are the major producer of IFN-γ during T. congolense infection ( 16 , 22 , 23 ) and excessive production of IFN-γ kills infected BALB/c mice ( 17 ), a strategy was developed with the aim to maintain an optimal production of IFN-γ by partial depletion of CD4 + T cells using high and low doses of ant-CD4 mAb ( 22 ). Strikingly, infected BALB/c mice partially (0.1 mg mAb), but not completely (4 mg mAb), depleted of CD4 + T cells had significantly decreased parasitemia and dramatically enhanced survival, accompanied with ~80% reduced production of IFN-γ ( 22 ).…”

“…IL-12 stimulates CD4 + T cells to produce IFN-γ via activation of STAT4 signaling ( 26 ), whereas IL-27 inhibits CD4 + T cells to secrete IFN-γ ( 24 ). Interleukin 10, mainly synthesized by CD4 + ( 22 , 23 , 27 ) and myeloid cells ( 28 ), inhibits IFN-γ production through downregulation of the secretion of IL-12 by direct modulation of mononuclear phagocytes ( 2 ). Protective role: IFN-γ enhances Kupffer cell phagocytosis of trypanosomes circulating in the bloodstream ( 12 , 13 ).…”

Design of an Epitope-Based Vaccine Ensemble for Animal Trypanosomiasis by Computational Methods

“…In comparison to the suggested protective role of CD4 + T cells, CD8 + T cells were described to have a parasite-promoting effect in a mouse model of experimental T. brucei infection [44]. But CD8 + T cell depletion in trypanosusceptible Boran cattle naturally infected with T. congolense through tsetse bites did not lead to any effect in the parasitemia or anemia, which is the main determinant of survival [3].…”