Negative regulation of expansion

Effector cells exist at high frequency only transiently during an immune response. Once the antigen/pathogen has been cleared (or in the event that it cannot be cleared), effector cells eventually stop proliferating and die. This negative regulation may prevent exceedingly strong and persistent immune responses that could be damaging to the host. In addition, the apoptosis of no-longer-needed effector cells may prevent the buildup of T cells that could dilute out naive responders and take up valuable space in the immune system.

The CTLA4 molecule appears to play a critical role in this negative regulation of clonal expansion. Unlike CD28, this receptor for B7 has been found to exert a negative effect on lymphocyte proliferation. CTLA4 expression is delayed following activation, corresponding to the time when the immune system begins to limit further lymphocyte expansion. Remarkably, CTLA4 homozygous-mutant mice (that do not express this molecule on their T cells) are found to have both an expansion of T lymphocytes and lymphoproliferative disease. Thus, ligation of CTLA4 by B7 may serve as an important control mechanism in limiting immune responses.

The principal mechanism for the eventual clearance of effector cells appears to be an activation-induced cell death (AICD). Persistent TCR signaling causes effector T cells to slowly upregulate the death receptor Eas and its counter-receptor Fas-ligand (FasL). This expression results in death of the T cell and other Fas4 cells, as Fas signaling triggers apoptosis. Interestingly, the mutant mouse strains lpr/lpr and gld/gld have defective Fas and Fasl , respectively, and their effector lymphocytes are resistant to AICD. This results in the accumulation of lymphocytes in these strains, which in turn appears to cause autoimmune disease. Thus, AICD may be essential to control the expansion of potentially deleterious effector cells.

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