Blocking the CD154–CD40 interaction with anti-CD154 antibody differentially regulates interleukin-4 synthesis in T cells and IgE production in B cells

ABSTRACTUsing severe combined immunodeficiency mice engrafted with peripheral blood mononuclear cells from atopic patients, we analyzed the regulatory effects of anti-CD154 antibody on the in vivo induction of human interleukin (IL)-4 and IgE expression. Although anti-CD154 treatment of engrafted mice abrogated mature Cε transcription and IgE production, IL-4 mRNA levels were enhanced by the treatment. In addition, anti-CD154-induced enhancement of intracellular IL-4 synthesis was detectable in both CD4+ and CD8+ T cell subsets. Furthermore, upregulation of germline Cε transcription could be seen in anti-CD154-treated mice. These results demonstrate that blocking the CD154-CD40 interaction with anti-CD154 differentially regulates IL-4 synthesis in T cells and IgE production in B cells. Our data also indicate that antibody ligation of CD154 on T cells causes enhanced synthesis of IL-4, thereby contributing to upregulation of germline Cε transcription in B cells

Regulation of Activated CD4+ T Cells by NK Cells via the Qa-1–NKG2A Inhibitory Pathway

SummaryThe ability of natural-killer cells to regulate adaptive immunity is not well understood. Here we define an interaction between the class Ib major histocompatibility complex (MHC) molecule Qa-1–Qdm on activated T cells responsible for adaptive immunity and CD94–NKG2A inhibitory receptors expressed by natural-killer cells by using Qa-1-deficient and Qa-1 knockin mice containing a point mutation that selectively abolishes Qa-1–Qdm binding to CD94–NKG2A receptors. The Qa-1–NKG2A interaction protected activated CD4+ T cells from lysis by a subset of NKG2A+ NK cells and was essential for T cell expansion and development of immunologic memory. Antibody-dependent blockade of this Qa-1–NKG2A interaction resulted in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis. These findings extend the functional reach of the NK system to include regulation of adaptive T cell responses and suggest a new clinical strategy for elimination of antigen-activated T cells in the context of autoimmune disease and transplantation

Induction of IgE synthesis by genetically modified CD8+ T cells of a patient with adenosine deaminase deficiency

We have previously reported that an adenosine deaminase (ADA)-deficient patient treated with T cell-directed gene therapy had an increase in serum IgE levels, despite a marked inversion of the CD4/CD8 ratio. In the present report, we have analyzed the phenotypic and functional profiles of the patient's lymphocytes obtained during the clinical trial. In peripheral blood mononuclear cells (PBMC) that were freshly prepared from the patient, both CD4+ and CD8+ T cell subsets were negative for CD40 ligand (CD40L; CD154) and Fas ligand (FasL; CD95L), while CD20+ B cells constitutively expressed CD40 and HLA-DR and were negative for CD80, CD86 and Fas (CD95). The expression of CD23 was detected on the majority of CD20+ B cells and expression was upregulated by interleukin (IL)-4. Furthermore, the patient's PBMC, which already expressed both germline and mature Ce transcripts in vivo, spontaneously secreted IgE and responded to IL-4 with increased IgE production during in vitro culture. When stimulated with anti-CD3ε monoclonal antibody (mAb), CD8+ T cells from gene-transduced T cells displayed high production of interferon (IFN)-γ, low production of IL-4 and IL-13 and comparable levels of CD40L and FasL expression; however, lined CD8+ T cells from circulating T cells expressing the transgene produced IL-4 and IL-13 together with smaller amounts of IFN-γ and preferably expressed CD40L rather than FasL. Two such CD8+ T cells, in conjunction with the presence of IL-4, supported CD40L-mediated B cell proliferation and IgE production after stimulation and fixation. These results indicate that ADA-deficient B cells are functionally mature and that gene-transduced CD8+ T cells and lined CD8+ T cells containing the transgene exhibit T helper 0- and T cytotoxic (c) 2-like phenotypes, respectively. Our data also suggest that immuno-logic reconstitution with genetically modified CD8+ T cells may promote IgE production