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Highlights: [•] CD4+ Treg develop in transgenic mice expressing mutant MHC II incapable of binding to CD4. [•] Relative numbers of CD25+CD4+ Treg are increased. [•] Activated Treg suppress IL-2 secretion in normally selected CD4+ T cells. [•] Treg suppression is contact-dependent. [ABSTRACT FROM AUTHOR]

Abstract: The ability of DCs to induce immune tolerance depends on its maturation status. RelB plays a pivotal role in DCs differentiation. A therapeutic protocol of DCs-based not only induces hyporesponsiveness in TNs, but also in alloreactive TMs is required. Thus, it is urgent to assess modulatory effects of RelB-silenced DCs on TMs and TNs. In this study, we constructed lentiviral vector which could efficiently silenced the RelB in DCs (DCs-miR RelB) to keep them immature. These DCs induced antigen-specific hyporesponsiveness in CD4+ TNs. In contrast, upon re-stimulation with mature DCs, CD4+ TMs primed by DCs-miR RelB maintained hyporesponsiveness in terms of proliferation and cytokine production. And these may be associated with micro155 and micro181a expression levels in TMs and TNs. These results may help developing the DCs-based therapeutical protocols by inducing hyporesponsiveness in CD4+ TNs and TMs. [Copyright &y& Elsevier]

The ability of DCs to induce immune tolerance depends on its maturation status. RelB plays a pivotal role in DCs differentiation. A therapeutic protocol of DCs-based not only induces hyporesponsiveness in T N s, but also in alloreactive T M s is required. Thus, it is urgent to assess modulatory effects of RelB-silenced DCs on T M s and T N s. In this study, we constructed lentiviral vector which could efficiently silenced the RelB in DCs (DCs-miR RelB) to keep them immature. These DCs induced antigen-specific hyporesponsiveness in CD4 + T N s. In contrast, upon re-stimulation with mature DCs, CD4 + T M s primed by DCs-miR RelB maintained hyporesponsiveness in terms of proliferation and cytokine production. And these may be associated with micro155 and micro181a expression levels in T M s and T N s. These results may help developing the DCs-based therapeutical protocols by inducing hyporesponsiveness in CD4 + T N s and T M s. [ABSTRACT FROM AUTHOR]

Abstract: We examined the role of the PD-1 pathway on the activation of naïve, memory, and recently activated human CD4+ T cells to test whether they responded differently. PD-1 ligand blockade modestly enhanced the percentage of responding T cells and production of IFN-γ in a primary response to myelin basic protein (MBP) in normal donors. PD-1 ligand blockade strongly enhanced proliferation and cytokine production by memory or recently activated T cells (tetanus toxoid and MBP). Blockade of PD-L1 alone had more effect than PD-L2, consistent with its higher expression on ex vivo dendritic cells; furthermore, anti-PD-L1 plus anti-PD-L2 resulted in the greatest enhancement. Moreover, PD-L1-Ig inhibited anti-CD3 induced activation of naïve, memory, and recently activated CD4+ T cells. Together, our data demonstrated PD-1 functioned as a negative regulatory pathway on naïve T cells during a primary response, and more potently, on memory or recently activated T cells during a secondary response. [Copyright &y& Elsevier]

Syngeneic mixed lymphocyte reaction (SMLR) has been considered to represent T cell response to self antigens. In this study using stimulator dendritic cells (DC), we analyzed cellular components responding to the syngeneic DC. It was shown that the predominant dividing cells were CD8+ T cells although the response of CD4+ T cells was essential for initiation of SMLR. In spite of the vigorous proliferation and expression of several activation markers, these SMLR-activated CD8+ T cells hardly killed syngeneic targets and most of the CD8+ T cells produced no interferon-γ upon restimulation with DC. Furthermore, in SMLR where CD8+ T cells were absent or inhibited, a considerable proliferation of CD4− CD8− double negative-T cells that included TCRα/β+ natural killer-T cells (NKT cells), TCRγ/δ+ NKT cells and TCRγ/δ+ T cells was observed. [Copyright &y& Elsevier]

Mechanisms of central and peripheral tolerance prevent autoimmunity. Regulatory T cells inhibit the activation of potentially auto-reactive T cells in peripheral lymphoid organs. In transgenic mice in which all MHC class II molecules are incapable of binding to CD4, class II MHC-restricted T cells preferentially differentiated into immunosuppressive, regulatory T cells. In these mutant MHC class II transgenic mice, a subset of CD4(+) T cells constitutively expressed moderately elevated levels of CD25 and potently inhibited interleukin-2 secretion by T cells from normal mice in a cell-to-cell, contact-dependent manner. Immunosuppressive activity depended on activation of the regulatory T cells. Thus, CD25(+)CD4(+) T cells from mutant MHC class II transgenic mice resembled phenotypically and functionally a major subset of natural regulatory T cells in normal mice, but were two to three-times more abundant. These results further clarify the mechanisms that govern the differentiation and maintenance of CD25(+)CD4(+) regulatory T cells, and present avenues for immunomodulation., (Copyright © 2013 Elsevier Inc. All rights reserved.)