Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases (HDAC) 1 and 2 as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of MHC class II-selected CD4+ helper T cells (TH) that expressed CD8 lineage genes such as Cd8a and Cd8b1. HDAC1-HDAC2-deficient TH0 and TH1 cells further up-regulated Cd8 lineage genes and acquired a CD8 effector program in a manner dependent on Runx-CBFβ complexes, while TH2 cells repressed CD8 lineage features independently of HDAC1 and HDAC2. These results demonstrate that HDAC1-HDAC2 maintain CD4 lineage integrity by repressing Runx-CBFβ complexes that otherwise induce a CD8-like effector program in CD4+ T cells.
Cd8a and Cd8b1 coreceptor gene (Cd8) expression is tightly controlled during T-cell development by the activity of five Cd8 enhancers (E8 I -E8 V ). Here we demonstrate a unique transcriptional program regulating CD8 expression during CD8 + effector T-cell differentiation. The Cd8 enhancer E8 I and Runx/core-binding factor-β (CBFβ) complexes were required for the establishment of this regulatory circuit, because E8 I -, Runx3-, or CBFβ-deficient CD8 + T cells down-regulated CD8α expression during activation. This finding correlated with enhanced repressive histone marks at the Cd8a promoter in the absence of E8 I , and the down-regulation of CD8α expression could be blocked by treating E8 I -, Runx3-, or CBFβ-deficient CD8 + T cells with the histone deacetylase inhibitor trichostatin A. Moreover, Runx/CBFβ complexes bound the Cd8ab gene cluster in activated CD8 + T cells, suggesting direct control of the Cd8a locus. However, CD8 + effector T cells maintained high levels of CD8α when CBFβ was conditionally deleted after activation. Thus, our data suggest an E8 I -and Runx3/CBFβ-dependent epigenetic programming of the Cd8a locus during T-cell activation, leading to Runx/ CBFβ complex-independent maintenance of CD8α expression in effector T cells.epigenetic marks | transcriptional control | cytotoxic T lymphocytes T he expression of the CD4 and CD8 coreceptors is linked with the functional phenotype of mature T cells. On conventional T cells, CD8 usually consist of CD8α and CD8β heterodimers (encoded by the closely linked Cd8a and Cd8b1 genes, respectively), and the expression of the Cd8 genes during T-cell development is regulated by the activity of at least five different cisregulatory elements (1). The first Cd8 enhancer identified, designated E8 I , is active in mature CD8 single-positive thymocytes and in CD8 + T cells, and in innate-like CD8αα + intraepithelial lymphocyte (IEL) of the gut (2, 3). The generation of E8 I -deficient mice revealed that E8 I is essential for CD8αα expression in γδTCR (T-cell receptor) IEL, while CD8 expression on conventional T cells was not impaired (4, 5). The Cd8 enhancer E8 II directs expression of a reporter transgene in double-positive (DP) thymocytes and CD8 + T cells (4), while E8 II -deficient mice have normal CD8 expression (6). Combined deletion of E8 I and E8 II leads to variegated expression of CD8 in DP thymocytes (6), and subsequent studies showed that CD8 variegation correlates with an epigenetic "off" state (7). A similar variegation phenotype is also observed in mice lacking the Cd8 enhancer E8 V (8). Another enhancer, E8 III , is active in DP thymocytes (4), and combined deletion of E8 II and E8 III resulted in a mild CD8 variegation phenotype in DP thymocytes, but E8 II ,E8 III -deficient mice have normal levels of CD8 on peripheral T cells (9). Taken together, these studies revealed a complex network of cis-regulatory elements, and link Cd8 enhancer functions with chromatin
Nuclear receptor corepressor 1 (NCOR1) is a transcriptional regulator bridging repressive chromatin modifying enzymes with transcription factors. NCOR1 regulates many biological processes, however its role in T cells is not known. Here we show that Cd4-Cre-mediated deletion of NCOR1 (NCOR1 cKOCd4) resulted in a reduction of peripheral T cell numbers due to a decrease in single-positive (SP) thymocytes. In contrast, double-positive (DP) thymocyte numbers were not affected in the absence of NCOR1. The reduction in SP cells was due to diminished survival of NCOR1-null postselection TCRβhiCD69+ and mature TCRβhiCD69− thymocytes. NCOR1-null thymocytes expressed elevated levels of the pro-apoptotic factor BIM and showed a higher fraction of cleaved caspase 3-positive cells upon TCR stimulation ex vivo. However, staphylococcal enterotoxin B (SEB)-mediated deletion of Vβ8+ CD4SP thymocytes was normal, suggesting that negative selection is not altered in the absence of NCOR1. Finally, transgenic expression of the pro-survival protein BCL2 restored the population of CD69+ thymocytes in NCOR1 cKOCd4 mice to a similar percentage as observed in WT mice. Together, these data identify NCOR1 as a crucial regulator of the survival of SP thymocytes and revealed that NCOR1 is essential for the proper generation of the peripheral T cell pool.
Pakistan has a large population of more than 150 million people with an overall carrier frequency of approximately 5.6% for beta-thalassemia. Punjab is the largest province of the country having more than 50% of the population. The state of beta-thalassemia is alarming as consanguinity is very high (>81%) and the literacy rate is low in South Punjab. A thalassemia prevention program is the need of the hour in this part of Pakistan. In this study, we initiated awareness, screening, and characterization of the mutations causing beta-thalassemia as well as a genetic counseling program mainly in the districts of Faisalabad and D.G. Khan to establish prenatal diagnosis, a facility previously unavailable in this region for disease prevention. A total of 248 unrelated transfusion-dependent children and the available members of their families were screened to characterize the mutations and identify the carriers. Genetic counseling was provided to these families and prenatal diagnosis offered. In the samples analyzed, 11 beta-thalassemia mutations and three hemoglobin variants were detected mainly by using the Monoplex and Multiplex ARMS-PCR. First-trimester prenatal diagnosis was carried out through chorionic villus sampling (CVS) in seven pregnancies at risk. As a result of our campaign, 145 carrier couples planning to have more children gave their consent to have retrospective prenatal diagnosis in every pregnancy in future. A cooperative trend and a positive attitude toward the prevention of beta-thalassemia were noticed in the families with affected children and in the general population.
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