Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.

Abstract

SummaryCognate interactions between antigen-presenting B and T cells play crucial roles in immunologic responses. T cells that have been activated via the crosslinking of CD3 are able to induce B cell proliferation and immunoglobulin secretion in a major histocompatibility complex-unrestricted and contact-dependent manner. We find that such activated human CD4 + T cells, but not control Ig-treated T cells, may induce normal or leukemic B cells to express B7/BB1 and significantly higher levels of CD54 intercellular adhesion molecule 1 via a process that also requires direct cell-cell contact. To discern what cell surface molecule(s) may be responsible for signalling B cells to express B7/BB1, we added various monoclonal antibodies (mAbs) specific for T or B cell accessory molecules or control mAbs to cocultures of c~-CD3-activated T cells and resting B cells. We find that only ol-CD40 mAbs can significantly inhibit the increased expression of B7/BB1, suggesting that the ligand for CD40 expressed on activated T ceils may be an important inducer of B7/BB1 expression. Subsequent experiments in fact demonstrate that cr mAbs, but not control mAbs, induce changes in B cell phenotype similar to those induced by activated T cells when the mAbs are presented on Fc"/RII (CDw32)-expressing L ceils. These phenotypic changes have significant effects on B cell function. Whereas chronic lymphocytic leukemia (CLL) B cells normally are very poor stimulators in allogeneic mixed lymphocyte reactions (MLRs), CLL-B ceils preactivated via CD40 crosslinking are significantly better presenters of aUoantigen, affecting up to 30-fold-greater stimulation of T cell proliferation than that induced by control treated or nontreated CLL-B cells. Similarly, the MLR of T cells stimulated by allogeneic nonleukemic B cells can be enhanced significantly if the stimulator B cells are preactivated via CD40 crosslinking. The enhanced MLR generated by such preactivated B ceils may be inhibited by blocking B7/BB1-CD28 interaction with CTLA4Ig. These studies demonstrate a novel, CD40-dependent pathway for inducing B cell expression of B7/BB1 and enhancing B cell antigenpresenting cell activity that can be initiated via cell-ceU contact with ot-CD3-stimulated CD4 + T cells.

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

“…It has been postulated that there is interdependence between the CD40-CD154 and CD28-B7 pathways, whereby acquisition of both signals is necessary for effective activation of the APC (39)(40)(41). In support of this, an up-regulation of CD80 and CD86 can be prevented by the administration of anti-CD154 (42), and CD28-B7 costimulation has been shown to be necessary to sustain CD154 expression (43). However an absolute requirement for CD28 costimulation for CD154 expression has not been universally reported (39,44).…”

Functional transfer of CD40L gene in human B-cell precursor ALL blasts by second-generation SIN lentivectors

“…18 The best available results so far for gene transduction have been obtained with second-generation lentiviral vectors monitoring the expression of the CD80 transgene up to 48 h. 5 More recently, second-generation lentiviral vectors have been further modified by deleting a portion of the U3 LTR region in the so-called self-inactivating vector (SIN) with improved safety, 8,9,15,19,20 and by the introduction of two cis-acting elements, one derived from the pol sequence, called central polypurine tract sequence (cPPT), 11,21,22 and the other, termed Wpre, obtained from the genome of the woodchuck hepatitis virus, both believed to increase transgene expression. [23][24][25] As previously demonstrated by our group 26 and others, [27][28][29][30][31][32] CD40 triggering by the CD40L molecule is capable of inducing a number of morphological and functional changes of BCP-ALL blasts, including the upregulation of the surface markers CD40, CD86, CD80, MHC class I and II, CD54 and CD58, and the secretion of chemoattractants MDC and TARC. Furthermore, data indicate that the transgenic expression of CD40L alone or in concomitance with other molecules in several hematological malignancies can elicit an antitumor immune response both in vitro and in vivo.…”

Rapid and efficient nonviral gene delivery of CD154 to primary chronic lymphocytic leukemia cells

“…3-9. Forced expression of CD154 in B-CLL cells can rescue their immunogenic function, and hIL-2 synergistically enhances this action. 4,5,7,19,21,27 To further demonstrate that the CD154-transfected B-CLL cells are functional, the control, mocktransfected and CD154-transfected B-CLL cells were mixed with allogeneic lymphocytes for 48 h together with hIL-2-transfected B-CLL cells (approximately 1 ng/ml hIL-2 expressed). Culture media were then analyzed for IFN-g production as an index of T-cell stimulation.…”

“…[1][2][3] Despite the strong expression of major histocompatibility complex I (MHC I) and class II (MHC II) molecules, the neoplastic B-CLL cells generally lack the surface expression of costimulatory molecules; thus, they are generally ineffective stimulator cells in mixed lymphocyte reactions. [3][4][5][6][7][8][9] CD154 (CD40L) belongs to the tumor necrosis factor superfamily 10,11 and is normally expressed transiently by activated CD4 T-helper lymphocytes. 12,13 It interacts with the receptor CD40 usually expressed by B cells, dendritic cells (DC) and other antigenpresenting cells (APC) to proliferate, differentiate, upregulate costimulatory molecules, such as CD80 and CD86, and adhesion molecules (e.g.…”

“…ICAM-I) to increase antigen presentation. 4,[13][14][15] CD154/CD40 interaction plays an essential role in the regulation of both humoral 16 and cellular immune responses. 17,18 Patients with B-CLL have a similar immunodeficiency as those observed in patients with inherited CD154 deficiency that their CD4 T cells fail to express CD154 upon ligation of CD3.…”