Distinct roles of helper T-cell subsets in a systemic autoimmune disease

Abstract

IntroductionThe interleukin-2 knockout (IL-2-KO) mouse provides a powerful model for defining the signals involved in the development of spontaneous autoimmune disease in the absence of regulatory T cells. IL-2-KO mice on the BALB/c background develop a systemic autoimmune disease, dying by 5 weeks from complications of autoimmune hemolytic anemia (AIHA). 1 The principal immunologic defects in these mice are a deficiency of regulatory T lymphocytes (Tregs) leading to a breakdown of self-tolerance and failure of T-cell homeostasis, resulting in uncontrolled activation and proliferation of CD4 ϩ T cells. 2,3 It has been shown that AIHA progression in these animals is mediated by autoantibodies and is dependent on abnormal helper T-cell (Th) activity. 1,4,5 We used this mouse model of spontaneous, acute systemic autoimmunity to define the cytokine milieu that influences the development of autoimmune disease.A tightly controlled balance between activation and suppression normally maintains immune homeostasis. Dysregulated cytokine expression is documented in various autoimmune and inflammatory diseases, and in the expansion of autoreactive T cells. 6-10 Our understanding of the cytokine network required to induce, amplify, and control self-reactive lymphocytes continues to evolve. Autoimmune manifestations have traditionally been thought to be mediated by Th1 cells and their abundant interferon-␥ (IFN-␥) and tumor necrosis factor (TNF) production. With the more recent identification of the Th17 subset, the role of cytokines in autoimmunity is being re-evaluated. Th17 cells are potent inducers of tissue inflammation, and dysregulated expression of IL-17 appears to initiate organ-specific autoimmunity; this has been best characterized in mouse models of colitis, 11 experimental autoimmune encephalomyelitis, 12 and rheumatoid arthritis. 13 The specific roles and interactions of Th subsets during the development of autoimmunity are a topic of great interest at present. 14,15 In this study, we set out to evaluate the contributions of Th1 and Th17 cytokines in the development of inflammation and autoimmunity in the absence of Tregs using the IL-2-KO mouse model. We demonstrate a clear role for IFN-␥ in the production of autoantibodies and progression of AIHA. In the absence of IFN-␥, IL-2-KO mice show delayed AIHA but, over time, develop intestinal inflammation, whereas elimination of IL-17 has no impact on the kinetics of AIHA development. Thus, our studies reveal that different cytokines play distinct roles in various manifestations of autoimmunity in the absence of Tregs. Methods MiceMice lacking IL-2, IFN-␥, IL-17, IL-2/CD28, IL-2/CD40L, IL-2/IFN-␥, and IL-2/IL-17 were used on the BALB/c background. Mice were bred and maintained in our specific pathogen-free facility at the Animal Barrier Facility in accordance with the guidelines of the Laboratory Animal Resource Center of the University of California San Francisco. Lymphocyte isolationLymph nodes (LNs) and spleens were pressed through a nylon mesh filter, red blood ...

In vitro‐induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sites

“…Therefore, we concluded that IL-17 might play a role in the late phase of inflammation only but not in the induction phase. This is in line with recently published data where Hoyer et al claimed that IL-17 plays a minor role in the induction phase but a major role in chronic tissue inflammation in the murine model of autoimmune haemolytic anaemia [30]. In 2006 several reports described the in vitro differentiation of Th17 cells from naïve T cells using the combination of IL-6 and TGF-b [7,9,31].…”

Functional characterization of CD4+ T cells in aplastic anemia

“…11,12 CD4 ϩ cells include IFN-␥-producing CD4 ϩ T cells (Th1 cells), IL-4-producing CD4 ϩ T cells (Th2 cells), regulatory T cells (Tregs), and IL-17-producing CD4 ϩ T cells (Th17 cells), all of which play a pivotal role in autoimmunity. 13,14 In AA, Tregs are reduced and express low levels of transcription factor Foxp3. 15,16 However, the Treg population is not uniform, and distinct subpopulations of human Tregs, demonstrating functional heterogeneity, 17 have been identified recently.…”

Partial tolerance of autoreactive B and T cells to erythrocyte-specific self-antigens in mice

“…33 These findings are consistent with models of spontaneous loss of humoral tolerance to RBC antigens in mice prone to develop AIHA. 34 In the current model, whatever the tolerance mechanisms may be, the RBC autoreactive B cells represent an intrinsically dangerous population, as all it takes is T-cell help to launch a full autoimmune antibody response.…”