Thymic selection pathway regulates the effector function of CD4 T cells

Li, Wei; Sofi, M. Hanief; Yeh, Norman; Sehra, Sarita; McCarthy, Brian P.; Patel, Dipak R.; Brutkiewicz, Randy R.; Kaplan, Mark H.; Chang, Cheong Hee

doi:10.1084/jem.20070321

Cited by 43 publications

(76 citation statements)

References 73 publications

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“…Similar phenotypes were reported on another type of innate-like CD4 T cell, which is induced by MHC class IIexpressing thymocytes (42,43). This type of innate-like CD4 T cells (T-CD4 T cells) showed rapid production of cytokines (especially Th2 cytokine) and exhibited reduced/suppressive activities of immune responses in vivo, resembling Bach2 −/− CD4 T cells (42,43). There might be a similar mechanism that determines the characteristics of Bach2-deficient and T-CD4 T cells.…”

Section: Discussionsupporting

confidence: 52%

“…S6), suggesting that Bach2 −/− T cells are not fully maturated as effector T cells. Similar phenotypes were reported on another type of innate-like CD4 T cell, which is induced by MHC class IIexpressing thymocytes (42,43). This type of innate-like CD4 T cells (T-CD4 T cells) showed rapid production of cytokines (especially Th2 cytokine) and exhibited reduced/suppressive activities of immune responses in vivo, resembling Bach2 −/− CD4 T cells (42,43).…”

Section: Discussionmentioning

confidence: 53%

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Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Tsukumo

Unno

Muto

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

151

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The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (−/−) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2 −/− naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2 −/− naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. Kruppel-like factor 2 (KLF2) is one of those TF, which regulates the expression of the sphingosine-1-phosphate receptor-1 (S1pr1) in SP cells (2). S1pr1 is required for the egress of SP cells from the thymus, and thus KLF2-deficient (−/−) SP cells accumulate in the thymus. KLF2 positively regulates S1pr1 expression through direct binding to its promoter. KLF2 −/− mice also develop an unusual population of innate-like CD8 +

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 53%

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Tsukumo

Unno

Muto

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

151

View full text Add to dashboard Cite

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“…ϩ SP T cells were selected as efficiently as in control mice, although the functionality of these cells was later questioned (33). In a normal mouse adult thymus, ϳ50,000 thymic epithelial cells are present and presumably able to mediate most thymocyte-positive selection by contacting several cells simultaneously and because of their high MHC expression density.…”

Section: Discussionmentioning

confidence: 95%

Peripheral T Lymphocytes Recirculating Back into the Thymus Can Mediate Thymocyte Positive Selection

Kirberg

Bosco

Deloulme

et al. 2008

The Journal of Immunology

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The thymus continuously produces T lymphocytes that contribute to the maintenance of the peripheral T cell pool. Since peripheral recirculating T cells represent a very minor population among total thymocytes in normal animals, the relationship between the thymus and secondary lymphoid organs is generally considered unidirectional. Recently, several reports have described the presence of recirculating T cells in the thymus, raising issues regarding their possible function. In this article, we show that the niche for recirculating T cells in the thymus, i.e., their absolute number, is the same in lymphopenic and normal mice. Using a novel combination of TCR-transgenic mice in which the ligand necessary for positive selection of host T cells is only expressed by transferred donor T cells, we show that mature T cells recirculating back to the thymus can mediate positive selection.

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“…reported that the level of IL-4 mRNA is high in CD4 single-positive thymocytes and NKT cells in the thymus [38]. Thus, IL-4 signaling might be involved in the regulation of nTreg development.…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ‐STAT1 signal regulates the differentiation of inducible Treg: Potential role for ROS‐mediated apoptosis

et al. 2009

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Regulatory CD41 T cells are important for the homeostasis of immune cells, and their absence correlates with autoimmune disorders. However, how the immune system regulates Treg homeostasis remains unclear. We found that IFN-c-deficient-mice had more forkhead box P3 (FOXP3 1) cells than WT mice in all secondary lymphoid organs except the thymus. However, T-bet-or IL-4Ra-deficient mice did not show a similar increase. In vitro differentiation studies showed that conversion of naïve T cells into FOXP3 1 cells (neo-generated inducible Treg (iTreg)) by TGF-b was significantly inhibited by IFN-c in a STAT-1-dependent manner. Moreover, an in vivo adoptive transfer study showed that inhibition of FOXP3 1 iTreg generation by IFN-c was a T-cell autocrine effect. This inhibitory effect of IFN-c on iTreg generation was significantly abrogated after N-acetyl-L-cysteine treatment both in vitro and in vivo, indicating that IFN-c regulation of iTreg generation is dependent on ROS-mediated apoptosis. Therefore, our results suggest that autocrine IFN-c can negatively regulate the neo-generation of FOXP3 1 iTreg through ROSmediated apoptosis in the periphery.

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Thymic selection pathway regulates the effector function of CD4 T cells

Cited by 43 publications

References 73 publications

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Peripheral T Lymphocytes Recirculating Back into the Thymus Can Mediate Thymocyte Positive Selection

IFN‐γ‐STAT1 signal regulates the differentiation of inducible Treg: Potential role for ROS‐mediated apoptosis

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