Inactivation of T-Cell Responses

INACTIVATION OF T-CELL RESPONSES

Normal immune responses are tightly regulated. As the goal of the immune response (elimination of nonself) is achieved, downregulatory systems become operative and turn off the response. Two main downregulating systems able to turn off T cells have been de-scribed.

The best known of the two involves an alternative ligand for CD80/CD86, CTLA-4. In vitro this ligand is expressed 48–72 hours after exposure of T cells to activating signals. The interaction of CD80/CD86 with CTLA-4 results in inhibition of early TcR signaling events. This blocking seems associated with direct binding of CTLA-4 to the TcR ζ chain, which results in recruitment of a tyrosine phosphatase known as SHP-1. SHP-1 appears to dephosphorylate the protein kinases (particularly ZAP-70) involved in the activation path-way controlling the assembly of functional NF-AT/AP-1 complexes. In the absence of those complexes, the IL-2 gene will cease to be expressed. The importance of downregu-lating immune responses is underlined by the fact that laboratory mice deficient in CTLA-4 develop lethal lymphoproliferative disorders.

A second downregulating system has been recently identified. It involves molecules that inactivate or block the activation of STAT transcription factors. It is not clear whether these molecules dephosphorylate JAK and other kinases, or whether they dephosphorylate STAT factors directly.

Finally, Fas-FasL interactions, also play sig-nificant downregulating roles by eliminating activated cells expressing high levels of Fas.