CD8 + T cells drive autoimmune hematopoietic stem cell dysfunction and bone marrow failure

Abstract

Bone marrow (BM) failure syndrome encompasses a group of disorders characterized by BM stem cell dysfunction, resulting in varying degrees of hypoplasia and blood pancytopenia, and in many patients is autoimmune and inflammatory in nature. The important role of T helper 1 (Th1) polarized CD4+ T cells in driving BM failure has been clearly established in several models. However, animal model data demonstrating a functional role for CD8+ T cells in BM dysfunction is largely lacking and our objective was to test the hypothesis that CD8+ T cells play a non-redundant role in driving BM failure. Clinical evidence implicates a detrimental role for CD8+ T cells in BM failure and a beneficial role for Foxp3+ regulatory T cells (Tregs) in maintaining immune tolerance in the BM. We demonstrate that IL-2-deficient mice, which have a deficit in functional Tregs, develop spontaneous BM failure. Furthermore, we demonstrate a critical role for CD8+ T cells in the development of BM failure, which is dependent on the cytokine, IFNγ. CD8+ T cells promote hematopoietic stem cell dysfunction and depletion of myeloid lineage progenitor cells, resulting in anemia. Adoptive transfer experiments demonstrate that CD8+ T cells dramatically expedite disease progression and promote CD4+ T cell accumulation in the BM. Thus, BM dysregulation in IL-2-deficient mice is mediated by a Th1 and IFNγ-producing CD8+ T cell (Tc1) response.

CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease

“…IL-2-KO T cells were adoptively transferred as previously described (4). 1×10 6 CD4 T cells, 2×10 6 CD8 T cells, or a combination of each were transferred into TCRα-KO mice via eye injection.…”

“…Autoimmunity in the IL-2-deficient (KO) mouse model results from reduced T regulatory (Treg) frequency and functionality (1–3), promoting dysregulation of the T effector response. CD4 T helper type 1 (Th1) cells subsequently promote the production of anti-RBC IgG antibodies and bone marrow failure dependent on IFNγ secretion (4–6). While there is a clearly established role for CD4 T helper cells in promoting antibody-mediated disease, the importance of CD8 T cells in these diseases has been less explored.…”

T cell and peripheral blood parameters define progression of autoimmune disease in the IL-2Rα KO model

“…IL-2-KO mice develop severe BMF that contributes to the severe anemia in these mice (5, 26). We observed defects in the BM of IL-2Rα-KO mice indicative of BMF, including increased frequencies of HSC, CLP, and GMP, and reduced CMPs.…”

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

“…Although T cells have been suggested to be key mediators of marrow cytopenias, these studies have mostly been associative rather than demonstrating direct causation (15,16,28). To address whether the expansion or recruitment of effector T cells was required for BMF, we transplanted NSG (NOD/scid/gamma) mice, which are deficient in functional T, B and NK cells, with wild-type HSPC transduced with TIRAP or control in the absence of wild-type competing cells to avoid wild-type T cell expansion.…”

“…On the one hand IFNγ has been suggested to recruit T cells that mediate cytopenias through immune destruction of hematopoietic cells. On the other hand, T cells have been suggested to produce IFNγ which is postulated to result in death of marrow cells (15,16). More recently, IFNγ has been shown to inhibit thrombopoietin (TPO) and possibly erythropoietin (EPO) signaling through their cognate receptors by forming heterodimeric complexes and interfering with ligandreceptor interactions, thereby leading to impaired megakaryocytic and erythroid differentiation (17,18).…”