Group I mGlu receptor stimulation inhibits activation-induced cell death of human T lymphocytes

1. The effects of L-glutamate on activation-induced cell death (AICD) of human activated (1 μg ml ^-1 phytohemagglutinin plus 2 U ml ^-1 interleukin-2; 8 days) T lymphocytes were studied by measuring anti-CD3 monoclonal antibody (10 μg ml ^-1; 18 h)-induced cell apoptosis (Annexin V and propidium iodide staining). 2. L-Glutamate (1 × 10 ^-8-1 × 10 ^-4 M) significantly (P≤0.01) inhibited AICD in a concentration-dependent manner (EC ₅₀=6.3 × 10 ^-8 M; maximum inhibition 54.8±6.3% at 1 × 10 ^-6 M). 3. The L-glutamate inhibitory effect was pharmacologically characterized as mediated by group I mGlu receptors, since mGlu receptor agonists reproduced this effect. The EC ₅₀ values were: 3.2 × 10 ^-7 M for (1S,3R)-ACPD; 4.5 × 10 ^-8 M for quisqualate; 1.0 × 10 ^-6 M for (S)-3,5-DHPG; 2.0 × 10 ^-5 M for CHPG. 4. Group I mGlu receptor antagonists inhibited the effects of quisqualate 1.0 × 10 ^-6 M. The IC ₅₀ values calculated were: 8.7 × 10 ^-5, 4.3 × 10 ^-6 and 6.3 × 10 ^-7 M for AIDA, LY 367385 and MPEP, respectively. 5. L-Glutamate (1 × 10 ^-6 M; 18 h) significantly (P≤0.05) inhibited FasL expression (40.8±11.3%) (cytofluorimetric analysis), whereas it did not affect Fas signalling. 6. Expression of both mGlu ₁ and mGlu ₅ receptor mRNA by T lymphocytes and T-cell lines, as demonstrated by reverse transcriptase-PCR analysis, suggests that L-glutamate-mediated inhibition of AICD was exerted on T cells. 7. These data depict a novel role for L-glutamate in the regulation of the immune response through group I mGlu receptor-mediated mechanisms.