T Cell-Intrinsic Expression of c-Rel Regulates Th1 Cell Responses Essential for Resistance toToxoplasma gondii

Abstract

The ability of many microbial and inflammatory stimuli to activate members of the Rel/NF-κB family of transcription factors is associated with the regulation of innate and adaptive responses required to control infection. Individual family members play distinct roles during different infectious and inflammatory responses. For example, c-Rel is essential for the production of IL-12 in response to LPS, but dispensable for IL-12 production in response to Toxoplasma Ag. To assess the role of c-Rel during immunity to the intracellular pathogen Toxoplasma gondii, wild-type (WT) and c-Rel−/− mice were infected with Toxoplasma and the immune response was analyzed. c-Rel−/− mice developed severe toxoplasmic encephalitis with increased numbers of parasites compared with WT controls and succumbed to infection within 5–8 wk. Although increased susceptibility of c-Rel−/− mice was associated with decreased T cell activation, proliferation, and production of IFN-γ, these mice were able to generate Th1 effector cells that were present in the brain during chronic infection. In vitro mixing studies using WT and c-Rel−/− dendritic cells and WT and c-Rel−/− TCR transgenic T cells indicated that c-Rel−/− dendritic cells are defective in their ability to stimulate T cell responses. However, when c-Rel−/− T cells were transferred into T cell-deficient hosts, early defects in T cell activation, proliferation, and IFN-γ production persisted, and these mice remained susceptible to infection. Together, these studies indicate that although c-Rel is an important regulator of innate immune responses, it also plays an important role in optimization and maintenance of adaptive T cell responses during infection.

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Despite its ubiquitous expression, the absence of p105 is tolerated during embryonic development and is compatible with neonatal and adult viability (Sha et al, 1995). In addition to a mild learning deficit (Meffert and Baltimore, 2005), loss of NF-kB p50/p105 function is associated with defects in stress responses, Hu et al (1999), Li et al (1999a), Takeda Grumont et al (1998Grumont et al ( , 1999, Cheng et al (2003), Pohl et al (2002) T cells: defects in CD4 and CD8 T-cell responses, Th1 development and cytokine production (IL-2 and GM-CSF) in CD4 + T-cell responses Hilliard et al (2002), Lamhamedi-Cherradi et al (2003), Mason et al (2004), Gerondakis et al (1996), Rao et al (2003) Horwitz et al (1997) rela À/À c-rel À/À Yes (BE13) Multiple hemopoietic defects. Radiation chimeras exhibit nucleated erythrocytes, reduced number of B cells, systemic expansion of granulocytes and a reduction in monocytes Grossmann et al (1999Grossmann et al ( , 2000 T cells exhibit a cell-cycle block early in G1 resulting from a failure to undergo c-Myc-dependent growth Grumont et al (2004) rela À/À c-rel À/ À tnf À/À Neonatal E18 embryos exhibit multiple epidermal defects that include a failure to form specific hair types, disorganized basal Gugasyan et al (2004) Knockout and transgenic models for NF-jB pathway S Gerondakis et al plus impaired innate and adaptive immune function.…”

“…During CD4 þ T-cell responses, c-Rel regulates Th1 development plus quantitative and qualitative aspects of cytokine expression in response to microbial challenge (Mason et al, 2004), in pathogenic models of CNS inflammation (Hilliard et al, 2002), in streptozotocin-induced type I diabetes (Lamhamedi-Cherradi et al, 2003) and during islet allograft rejection (Yang et al, 2002). Whereas c-Reldependent production of IL-12 by professional APC, such as DC (Grumont et al, 2001), has been shown to be important in skewing the development of Th1 responses in experimentally induced EAE (Hilliard et al, 2002), c-Rel function is dispensable for generating Th1 cells and APC-dependent production of IL-12 when challenged with T. gondii (Mason et al, 2004). Instead, the impaired Th1 response seen in c-rel À/À mice infected with T. gondii appears to result from T-cell-intrinsic defects associated with the defective clonal expansion of Th1 effector cells (Mason et al, 2004).…”

“…Whereas c-Reldependent production of IL-12 by professional APC, such as DC (Grumont et al, 2001), has been shown to be important in skewing the development of Th1 responses in experimentally induced EAE (Hilliard et al, 2002), c-Rel function is dispensable for generating Th1 cells and APC-dependent production of IL-12 when challenged with T. gondii (Mason et al, 2004). Instead, the impaired Th1 response seen in c-rel À/À mice infected with T. gondii appears to result from T-cell-intrinsic defects associated with the defective clonal expansion of Th1 effector cells (Mason et al, 2004). c-Rel function is also important for regulating the T-cell-dependent production of cytokines.…”

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

“…Interferon gamma produced by TH1 cells in T. gondii infected mice has been shown to activate macrophages to kill this intracellular parasite and thereby contribute towards protection [4]. However these studies evaluated protective immunity against T. gondii following the intra-peritoneal route of infection rather than the peroral route, which is the natural route of infection.…”

A single NFκB system for both canonical and non-canonical signaling

“…Thus, these studies showed an essential role for cRel in B-and T-lymphocyte functions, cell types in which it is highly expressed. crel −/− mice are not lethal but show several defects, including defects in the cell cycle progression and survival in B cells, defects in CD4 and CD8 T-cell responses, and impaired cytokine production [18,19]. Further, dendritic cells lacking cRel:p50 are defective in CD40L-induced cell survival [20] and displayed reduced maturation phenotype [21].…”