Yumei Xiong

The Zinc Finger Transcription Factor Zbtb7b Represses CD8-Lineage Gene Expression in Peripheral CD4+ T Cells

How CD4-CD8 differentiation is maintained in mature T cells is largely unknown. The present study has examined the role in this process of the zinc finger protein Zbtb7b, a critical factor for the commitment of MHC II-restricted thymocytes to the CD4+ lineage. We showed that Zbtb7b acted in peripheral CD4+ T cells to suppress CD8-lineage gene expression, including that of CD8 and cytotoxic effector genes perforin and Granzyme B, and was important for the proper repression of interferon-gamma (IFN-gamma) during effector differentiation. The inappropriate expression of IFN-gamma by Zbtb7b-deficient CD4+ T cells required the activities of Eomesodermin and Runx transcription factors. Runx activity was needed for Granzyme B expression, indicating that Runx proteins control expression of the cytotoxic program. We conclude that a key function of Zbtb7b in the mature CD4+ T cell compartment is to repress CD8-lineage gene expression.

Control of the development of CD8[alpha][alpha]+ intestinal intraepithelial lymphocytes by TGF-[beta]

The molecular mechanisms directing the development of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (IEL) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ+CD8αα+ IEL. Mice with either a TGF-β1 null mutation or a T cell-specific deletion of the TGF-β receptor I lacked TCRαβ+CD8αα+ IEL, whereas transgenic mice that over-expressed TGF-β1 had an increased population of TCRαβ+CD8αα+ IEL. Defective development of the TCRαβ+CD8αα+ IEL thymic precursors (CD4-CD8-TCRαβ+CD5+) was observed in the absence of TGF-β. In addition, we showed that TGF-β signaling induced CD8α expression in TCRαβ+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. These data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ+CD8αα+ IEL and the expression of CD8 in T cells.The molecular mechanisms that direct the development of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (IELs) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ+CD8αα+ IELs. Mice with either a null mutation in the gene encoding TGF-β1 or T cell–specific deletion of TGF-β receptor I lacked TCRαβ+CD8αα+ IELs, whereas mice with transgenic overexpression of TGF-β1 had a larger population of TCRαβ+CD8αα+ IELs. We observed defective development of the TCRαβ+CD8αα+ IEL thymic precursors (CD4−CD8−TCRαβ+CD5+) in the absence of TGF-β. In addition, we found that TGF-β signaling induced CD8α expression in TCRαβ+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. Our data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ+CD8αα+ IELs and the expression of CD8α in T cells.

The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus

The transcription factor Ets1 contributes to the differentiation of CD8 lineage cells in the thymus, but how it does so is not understood. In this study, we demonstrate that Ets1 is required for the proper termination of CD4 expression during the differentiation of major histocompatability class 1 (MHC I)–restricted thymocytes, but not for other events associated with their positive selection, including the initiation of cytotoxic gene expression, corticomedullary migration, or thymus exit. We further show that Ets1 promotes expression of Runx3, a transcription factor important for CD8 T cell differentiation and the cessation of Cd4 gene expression. Enforced Runx3 expression in Ets1-deficient MHC I–restricted thymocytes largely rescued their impaired Cd4 silencing, indicating that Ets1 is not required for Runx3 function. Finally, we document that Ets1 binds at least two evolutionarily conserved regions within the Runx3 gene in vivo, supporting the possibility that Ets1 directly contributes to Runx3 transcription. These findings identify Ets1 as a key player during CD8 lineage differentiation and indicate that it acts, at least in part, by promoting Runx3 expression.

The sequential activity of Gata3 and Thpok is required for the differentiation of CD1d-restricted CD4+ NKT cells.

While most CD4+ T cells are MHC class II‐restricted, a small subset, including the CD1d‐restricted ‘invariant’ NKT (iNKT) cells, are selected on non‐classical MHC‐I or MHC‐I‐like molecules. We previously showed that the sequential activity of two zinc finger transcription factors, Gata3 and Thpok, promotes the differentiation of conventional, MHC II‐restricted thymocytes into CD4+ T cells. In the current study, we show that a Gata3‐Thpok cascade is required for the differentiation of CD4+ iNKT cells. Gata3 is required for iNKT cells to express Thpok, whereas Thpok is needed for proper NKT cell differentiation, and notably for NKT cells to maintain CD4 and terminate CD8 expression. These findings identify the sequential activity of Gata3 and Thpok as a hallmark of CD4+ T‐cell differentiation, regardless of MHC restriction.

Control of the development of CD8αα + intestinal intraepithelial lymphocytes by TGF-β

The molecular mechanisms directing the development of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (IEL) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ+CD8αα+ IEL. Mice with either a TGF-β1 null mutation or a T cell-specific deletion of the TGF-β receptor I lacked TCRαβ+CD8αα+ IEL, whereas transgenic mice that over-expressed TGF-β1 had an increased population of TCRαβ+CD8αα+ IEL. Defective development of the TCRαβ+CD8αα+ IEL thymic precursors (CD4-CD8-TCRαβ+CD5+) was observed in the absence of TGF-β. In addition, we showed that TGF-β signaling induced CD8α expression in TCRαβ+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. These data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ+CD8αα+ IEL and the expression of CD8 in T cells.The molecular mechanisms that direct the development of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (IELs) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ+CD8αα+ IELs. Mice with either a null mutation in the gene encoding TGF-β1 or T cell–specific deletion of TGF-β receptor I lacked TCRαβ+CD8αα+ IELs, whereas mice with transgenic overexpression of TGF-β1 had a larger population of TCRαβ+CD8αα+ IELs. We observed defective development of the TCRαβ+CD8αα+ IEL thymic precursors (CD4−CD8−TCRαβ+CD5+) in the absence of TGF-β. In addition, we found that TGF-β signaling induced CD8α expression in TCRαβ+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. Our data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ+CD8αα+ IELs and the expression of CD8α in T cells.

A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4+ T cells

The transcription factor ThPOK promotes CD4+ T cell differentiation in the thymus. Here, using a mouse strain that allows post-thymic gene deletion, we show that ThPOK maintains CD4+ T lineage integrity and couples effector differentiation to environmental cues after antigenic stimulation. ThPOK preserved the integrity and amplitude of effector responses and was required for proper differentiation of types 1 and 2 helper T cells in vivo by restraining the expression and function of Runx3, a nuclear factor crucial for cytotoxic T cell differentiation. The transcription factor LRF acts redundantly with ThPOK to prevent the transdifferentiation of mature CD4+ T cells into CD8+ T cells. As such, the ThPOK-LRF transcriptional module was essential for CD4+ T cell integrity and responses.

The enigma of CD4 lineage specification

CD4+ T cells are essential for defenses against pathogens and affect the functions of most cells involved in the immune response. Although CD4+ T cells generally recognize peptide antigens bound to MHC‐II molecules, important subsets are restricted by other MHC or MHC‐like molecules, including CD1d‐restricted “invariant” iNK T cells. This review discusses recently identified nodes in the transcriptional circuits that are involved in controlling CD4+ T‐cell differentiation, notably the commitment factor Thpok and its interplay with Runx transcriptional regulators, and focuses on how transcription factors acting upstream of Thpok, including Gata3, Tox and E‐box proteins, promote the emergence of CD4‐lineage‐specific gene expression patterns.

Thpok-independent repression of Runx3 by Gata3 during CD4+ T-cell differentiation in the thymus.

CD4+ helper T cells are essential for immune responses and differentiate in the thymus from CD4+CD8+ “double‐positive” (DP) thymocytes. The transcription factor Runx3 inhibits CD4+ T‐cell differentiation by repressing Cd4 gene expression; accordingly, Runx3 is not expressed in DP thymocytes or developing CD4+ T cells. The transcription factor Thpok is upregulated in CD4‐differentiating thymocytes and required to repress Runx3. However, how Runx3 is controlled at early stages of CD4+ T‐cell differentiation, before the onset of Thpok expression, remains unknown. Here we show that Gata3, a transcription factor preferentially and transiently upregulated by CD4+ T‐cell precursors, represses Runx3 and binds the Runx3 locus in vivo. Accordingly, we show that high‐level Gata3 expression and expression of Runx3 are mutually exclusive. Furthermore, whereas Runx3 represses Cd4, we show that Gata3 promotes Cd4 expression in Thpok‐deficient thymocytes. Thus, in addition to its previously documented role in promoting CD4‐lineage gene‐expression, Gata3 represses CD8‐lineage gene expression. These findings identify Gata3 as a critical pivot of CD4‐CD8 lineage differentiation.

Maintaining CD4-CD8 lineage integrity in T cells: where plasticity serves versatility

The divergence of the two αβ T cell subsets defined by the mutually exclusive expression of CD4 and CD8 glycoproteins is an important event during the intrathymic differentiation of T lymphocytes. This reviews briefly summarizes the mechanisms that promote commitment to the CD4 or CD8 lineage in the thymus, and discusses the transcription factor circuits and epigenetic mechanisms that concur to maintain lineage integrity in post-thymic cells and yet allow effector cell differentiation.

Control of CD8αα intestinal intraepithelial lymphocyte development by TGF-β

The molecular mechanisms directing the development of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (IEL) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ+CD8αα+ IEL. Mice with either a TGF-β1 null mutation or a T cell-specific deletion of the TGF-β receptor I lacked TCRαβ+CD8αα+ IEL, whereas transgenic mice that over-expressed TGF-β1 had an increased population of TCRαβ+CD8αα+ IEL. Defective development of the TCRαβ+CD8αα+ IEL thymic precursors (CD4-CD8-TCRαβ+CD5+) was observed in the absence of TGF-β. In addition, we showed that TGF-β signaling induced CD8α expression in TCRαβ+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. These data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ+CD8αα+ IEL and the expression of CD8 in T cells.The molecular mechanisms that direct the development of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (IELs) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ+CD8αα+ IELs. Mice with either a null mutation in the gene encoding TGF-β1 or T cell–specific deletion of TGF-β receptor I lacked TCRαβ+CD8αα+ IELs, whereas mice with transgenic overexpression of TGF-β1 had a larger population of TCRαβ+CD8αα+ IELs. We observed defective development of the TCRαβ+CD8αα+ IEL thymic precursors (CD4−CD8−TCRαβ+CD5+) in the absence of TGF-β. In addition, we found that TGF-β signaling induced CD8α expression in TCRαβ+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. Our data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ+CD8αα+ IELs and the expression of CD8α in T cells.