Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

Abstract

IntroductionAcquired aplastic anemia (AA), characterized by pancytopenia in peripheral blood (PB) and bone marrow (BM) hypoplasia, is a bone marrow failure syndrome attacked by autologous T cells, such as CD8 ϩ cytotoxic T cells, CD4 ϩ Th1 cells, and Th17 cells, on BM hematopoietic progenitors. [1][2][3][4] Hematopoiesis recovery after successful immunosuppressive treatment provided powerful evidence for the core role of the immune-mediated destruction of hematopoietic progenitor/stem cells. Mechanisms of immunemediated destruction of hematopoiesis include Th1 polarization response conferring immoderate production of inhibitory cytokines such as interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and interleukin-2 (IL-2), direct toxicity to autologous CD34 ϩ cells by T-cell populations, and Th17 immune response. [4][5][6][7] In that sense, AA is a specific autoimmune disease because of aberrant T-cell immune homeostasis and BM is the main target organ.It is now well established that CD4 ϩ T-cell subpopulations constitutively expressing the surface protein CD25 and the transcription factor FoxP3 are indispensable for the maintenance of immunologic self-tolerance and immunosuppression. [8][9][10][11] There is also accumulating evidence that impaired function of CD4 ϩ CD25 ϩ regulatory T cells (Tregs) has been implicated in the development of several common autoimmune diseases, 8,10 myelodysplastic syndromes, 12 and AA. 13 Until now, the only report of Treg abnormality in AA has shown that the numbers of circulating Tregs decreased in most patients. Meanwhile, almost all patients had low levels of nuclear factor of activated T cells, cytoplasmic 2 (NFAT1/ NFATc2) which could explain decreased FoxP3 expression in Tregs from AA patients. 13 But little is known regarding the function of Tregs in AA.Physiologically, induction of immune tolerance and suppression of autoreactive effector T-cell proliferation were the critical function of CD4 ϩ CD25 ϩ Tregs through cell contact-inhibition mechanisms and/or production of inhibitory cytokine. Furthermore, BM is a reservoir for CD4 ϩ CD25 ϩ Tregs that home to and are retained in BM through the stromal-derived factor-1␣ (SDF-1␣)/ CXCR4 signal. 14 Previous data demonstrated that the only way for Tregs homing to BM was via the SDF-1␣/CXCR4 signal. 14,15 It was believed that CXCR4 was the only receptor of SDF-1␣ for years. However, several reports recently provided evidence that SDF-1␣ also bound to another 7 transmembrane span receptor CXCR7. 16,17 Thus, the role of the SDF-1␣/CXCR4 axis in regulating Treg trafficking between BM and PB becomes more complex. Combined with the fact that BM is the target organ attacked by autoreactive effector T cells leading to hematopoiesis destruction, we hypothesized that Tregs in AA might have impaired homing potential to BM so as to be less efficient to suppress the effector T-cell proliferation and Th1-type cytokine production. We also hypothesized that Tregs in AA had intrinsic deficiencies of immunosuppression for autologous effector T...

Identification of novel microRNA signatures linked to acquired aplastic anemia

“…41 In AA patients, regulatory T cells are decreased in number and functionally abnormal. 42 Down-regulation of miR-126-3p in CD4 + T cells might partly explain the reduced induction and suppressive function of regulatory T cells in AA. MiR-223-3p reduces the commitment of erythroid progenitors and has a crucial role in granulocyte progenitor proliferation and function, and its expression is activated in neutrophils.…”

Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment

“…[8][9][10][11] Tregs from AA patients also secrete pro-inflammatory cytokines. 8 Correlation between number and function of Tregs and response to standard IST has not been fully investigated, and it is unclear whether the dominant Treg subpopulation in AA is more of a T conventional (T con ) subtype or are genuinely functional Tregs.…”

Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia

“…+ Treg number, an impaired suppressive function of Tregs on Tconvs, and the reduced trafficking of Tregs to the BM in patients with AA [12,13]. However, it remains unclear which phenotype best represents functional T r e g s i n h u m a n s .…”

“…Tregs effectively control the development and progression of autoimmune diseases such as type 1 diabetes and psoriasis [10,11]. Patients with immune-mediated BM failure such as AA have been shown to have significantly reduced numbers of Tregs [12,13]. However, it is unclear whether the decrease in the Treg count is actively involved in BM suppression through the failure to control autoreactive T cells in these diseases because the BM failure syndromes affect both myelopoiesis and lymphopoiesis; thus, the decrease in Tregs may merely represent T lymphocytopenia which occurs due to a decrease in the number of hematopoietic stem cells.…”