Manipulation of regulatory T cells and antigen-specific cytotoxic T lymphocyte-based tumour immunotherapy.

The most potent killing machinery in our immune system is the cytotoxic T lymphocyte (CTL). Since the possibility for self-destruction by these cells is high, many regulatory activities exist to prevent autoimmune destruction by these cells. A tumour (cancer) grows from the cells of the body and is tolerated by the body's immune system. Yet, it has been possible to generate tumour-associated antigen (TAA) -specific CTL that are also self-antigen specific in vivo, to achieve a degree of therapeutic efficacy. Tumour-associated antigen-specific T-cell tolerance through pathways of self-tolerance generation represents a significant challenge to successful immunotherapy. CD4(+)  CD25(+)  FoxP3(+) T cells, referred to as T regulatory (Treg) cells, are selected in the thymus as controllers of the anti-self repertoire. These cells are referred to as natural T regulatory (nTreg) cells. According to the new consensus (Nature Immunology 2013; 14:307-308) these cells are to be termed as (tTreg). There is another class of CD4(+) Treg cells also involved in regulatory function in the periphery, also phenotypically CD4(+)  CD25(±) , classified as induced Treg (iTreg) cells. These cells are to be termed as peripherally induced Treg (pTreg) cells. In vitro-induced Treg cells with suppressor function should be termed as iTreg. These different Treg cells differ in their requirements for activation and in their mode of action. The current challenges are to determine the degree of specificity of these Treg cells in recognizing the same TAA as the CTL population and to circumvent their regulatory constraints so as to achieve robust CTL responses against cancer.