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SIGNIFICIANCE OF THE CD2-INDUCED PATHWAY FOR ACTIVATION OF HUMAN LYMPHOCYTES EXPRESSING TCR-GAMMA / DELTA RECEPTORS AND EXECUTING NON-MHC-RESTRICTED CYTOTOXIC ACTIVITY

Objective


Soluble CD58, which was expressed and purified as a recombinant molecule, is a potent competitive inhibitor of the natural cell to cell interaction among CD2 expressing and CD58 expressing cells.

Some malignant cancer cells downregulate CD58 (adhesion molecule) and thus are not susceptible to lysis by autologous cytotoxic T lymphocytes. Blockade of CD2 CD58 interaction by recombinant material inhibits the function of effector cells. Exposure to soluble mediators such as tumour necrosis factor alpha, induces reexpression of CD58 on human tumour targets and, concomitantly, their susceptibility to autologous lymphocyte mediated cell lysis.

Mature CD4/CD8 positive were found to circulate in a patient suffering from severe aplastic anaemia (SAA). Extensive investigation demonstrated that these cells, following their expansion from patient blood suppressed autologous bone marrow differentiation in vitro. Aplastic anaemia may be due to an autoimmune type mechanism since CD8+/CD4+ cells were circulating in this patient exhibiting autocytotoxicity against bone marrow cultures and mature autologous lymphocytes.

It was found that the CD8 molecule which is present on these cells was clearly different from that which is usually found on human alpha/beta T cell receptor positive T cells. These clones represented an excellentexperimental tool to study the structure and function of a particular isoform of CD8 which is usually found on NK cells and gamma/delta cells, but not on alpha/beta T cells.
We shall study activation requirements of human Ti-gamma/delta T-lymphocytes and compare them with Ti-alapha/beta cells. To this end, in vitro systems as they exist in Heidelberg and Villejuif, will be employed, and responses to simulation with monoclonal antibodies, either alone or in combination, determined. Are effector functions and proliferative responses that are mediated through the T cell antigen-receptor differentially influenced by the existence or absence of the CD2-molecule on the respective effector cells? We shall also study influences of recombinant lymphokynes on activation of such cells via differential pathways.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

GERMAN CANCER RESEARCH CENTER
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Germany

Participants (1)

INSTITUT GUSTAVE ROUSSY
France