Veto Cells

Richard G Miller, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada

Veto cells were initially proposed on theoretical grounds as cells which could inactivate mature T lymphocytes that recognize them. One could regard them as antigen-presenting cells that inactivate rather than stimulate T cells that recognize them. Cells with this property could play a useful role in the establishment and maintenance of T cell tolerance to self anti gens, and in the downregulation of an immune response. Veto cells are readily distinguishable from T suppressor cells, which are thought to have a specific receptor; they regulate T cells they recognize via this receptor. With veto cells recognition is the other way. They carry specific antigen and regulate T cells on being recognized.

There is a growing body of experimental evidence for the existence of a veto cell that can delete cytotoxic T lymphocyte (CTL) precursors reactive against allogeneic class I major histocompatibility complex (MHC) molecules or against antigens presented in association with self class I MHC. Certain cells in bone marrow and in fetal liver, as well as CTLs themselves, can act as veto cells. Note that when any cell (including a CTL) acts as a veto cell, specificity is determined by the class 1 MHC molecule and associated peptide on the veto cell surface rather than the specificity of any T cell receptor which might be present on that cell.

Veto activity was first described in in vitro mixed lymphocyte cultures (MLC). Letting A, B and C be three MHC different inbred mouse strains, veto cells from strain A block CTL precursor activation when included in a B anti-A MLC but not when included in an A anti-B or B anti-C MLC. Studies in this system have led to the following conclusions:

1. Veto cells must carry the antigenic determinant (including the class I MHC restricting element) against which the response is being suppressed.

2. Veto cells act early in an immune response and produce functional deletion of CTL precursors capable of recognizing them. Deletion is probably physical, with death occurring by apoptosis. Veto cells are ineffective against mature CTLs.

3. Veto activity can occur in the presence of appropriate stimulatory antigen-presenting cells and lymphokines such as interleukin 2 (IL-2).

4. Cells carrying CD8 can act as veto cells. CD8 on the veto cell interacts with the a3 domain of the class I MHC on the recognizing T cell. This, in conjunction with the signal through the T cell receptor, leads to the death of the T cell.

What appears to be veto activity has also been demonstrated in vivo. CTL precursors reactive against allogeneic class I MHC molecules or against minor H antigens can be inactivated in vivo by injecting the host with viable CD8 T cells carrying those antigens. Survival of subsequent grafts carrying the same antigens as the injected T cells is greatly enhanced.

There are conflicting data as to whether there are veto cells capable of inactivating T cells restricted by or reactive against class II MHC. Note that if such veto cells do exist, they must necessarily carry class II MHC products and it is these products that would determine their specificity.

The in vivo role of veto cells remains unclear but they may be important in establishing/maintaining peripheral T cell tolerance and in immunoregulation.

See also: Cytotoxic T lymphocytes; Mixed lymphocyte reaction (MLR); T lymphocytes; Tolerance, peripheral.

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