Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse

Abstract

The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS) are controversial. Some studies have indicated an etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-γ, or ICSBP -a transcriptional protein involved in IFN signaling -to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-γ is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP -/-mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-γ and IL-12. Unexpectedly, however, the ICSBP -/-mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs.

The Role of CD4 T Cells in the Pathogenesis of Murine AIDS

“…Our result is in keeping with two other studies that also utilized more-direct approaches to examine the need for Th2 T cells in MAIDS: these studies found (i) that when mice with a genetic disruption of the IL-4 gene, but specifically fully backcrossed onto the susceptible B6 background, are used, MAIDS develops normally following LP-BM5 infection (35,36), and (ii) that B6 mice deficient in STAT6, which is the proximal signal transducer of ligated IL-4 receptor, also exhibited normal susceptibility to the induction of MAIDS (38).…”

“…In a recent follow-up study, we showed that the CD80/CD86 (B7.1/ B7.2) costimulatory ligands are not required for LP-BM5 induction of MAIDS (17). These results and other data (36) suggested that CD4 T-cell-expressed CD28 ligation is not required for the initiation of MAIDS or the early commitment to disease progression. Although this classic upregulation of CD80/CD86 after CD40 ligation is thus not necessary, we have used a panel of CD40 Tg mice on the CD40 ؊/؊ background to confirm that the CD40 signaling is required for MAIDS induction and is differentially mediated by TRAF binding to the TRAF 6 site (versus the TRAF 2/3/5 site) on the CD40 cytoplasmic tail (16).…”

“…1 and 3). Consideration of a possible differential role of Th1 versus Th2 cells as the required pathogenic CD4 T cells was pertinent, given the existing literature on both cytokine production specifically in MAIDS (11,35,36,38) and the critical function of Th1/Th2 CD4 T cells in various other disease states. Thus, in addition to playing differential roles in protection, polarized Th1-type and Th2-type responses are also responsible for different types of immunopathological reactions.…”

Defining the mechanism(s) of protection by cytolytic CD8 T cells against a cryptic epitope derived from a retroviral alternative reading frame

“…However, it has been reported by others that induction of LP-BM5 pathogenesis is correlated to high levels of IFNγ: specifically that B6 mice lacking IFNγ may have reduced MAIDS disease or require a prolonged time course to develop disease equivalent to w.t. susceptible B6 mice (Giese et al, 1996; Morawetz et al, 1998). To verify that the lack of disease observed in BALB/c IFNγ −/− mice was not instead due to an IFNγ-dependent pathogenic mechanism, we infected susceptible B6 mice lacking IFNγ with equivalent amounts of LP-BM5 and assessed disease severity, compared to w.t.…”

Murine AIDS requires CD154/CD40L expression by the CD4 T cells that mediate retrovirus-induced disease: Is CD4 T cell receptor ligation needed?

“…In a follow-up study, we demonstrated that B6 mice deficient for both the CD80/ CD86 (B7.1/B7.2) co-stimulatory ligands are susceptible to LP-BM5 induction of MAIDS (Green et al, 2002). These results on the APC (B cell) expressed B7 ligands, coupled with data from another laboratory on the CD80/CD86 receptor-CD4T cells expressed CD28 (Morawetz et al, 1998), suggested that CD28/CD80-CD86 interactions are not absolutely required for the initiation of MAIDS or the commitment to disease progression. Although the classic upregulation of CD80/CD86 after CD40 ligation is thus not necessary, we have used a panel of chimeric CD40 Tg mice on the CD40 -/background to confirm that the CD40 signaling is needed for MAIDS induction and is differentially mediated by TRAF binding to the TRAF 6 site (vs the TRAF 2/3/5 site) on the CD40 cytoplasmic tail (Green et al, 2004).…”