Chimeric proteins and methods of immunotherapy

A method of inducing death of a target cell, comprising:

• (a) expressing a system in a lymphocyte;
• and
• (b) contacting said target cell with the lymphocyte under conditions that induce said death of the target cell,
• wherein the system expressed in the lymphocyte comprises:
• (i) a chimeric transmembrane receptor polypeptide comprising a ligand binding domain, an immune cell signaling domain, and a gene modulating polypeptide (GMP), wherein the GMP comprises an actuator moiety linked to a cleavage recognition site;
• and
• (ii) a chimeric adaptor polypeptide comprising a receptor binding moiety linked to a cleavage moiety, wherein the cleavage moiety is capable of cleaving the cleavage recognition site on the receptor when the receptor binding moiety binds the receptor polypeptide in response to binding of the ligand binding domain to a ligand;
• wherein, upon contacting the target cell to the lymphocyte, the ligand binding domain binds a ligand present on the target cell to (i) activate cytotoxicity of the lymphocyte, and (ii) release the actuator moiety from the GMP via cleavage by the cleavage moiety at the cleavage site, wherein the actuator moiety in turn modulates expression and/or activity of an immune regulatory protein that enhances lymphocyte cytotoxicity and/or reduces a side effect of lymphocyte activation.