Surface T-cell Receptor Density is Critical for Cytolytic Activity Against MHClow Target Cells

D. FURMAN, E. VON EUW, M. BARRIO, E. LEVY, M. BIANCHINI, Y. LI,

Rio de Janeiro (Brasil)

Congreso; 13th International Congress of Immunology; 2007

The activation of T-cell effector functions requires clustering of a threshold number of T-cell receptors (TCRs) at the site of antigen presentation. An intermediate dwell-time of peptide-MHC (pMHC)/TCR interaction is also critical to achieve an adequate signalling for T-cell responsiveness. It is well known that many tumors and virus-infected cells can “hide” antigens by downregulating MHC molecules, thus escaping from T-cell recognition. However, strong evidence suggests that as few as 10 pMHC complexes suffice to activate T-cell function. Considering this evidence, how target cells can escape from the immune attack only by decreasing surface MHC molecules constitutes a paradox. We postulate that this escape mechanism can occur only when TCRlow T-cells interact with MHClow target cells. To test this hypothesis, we have sorted by FACS TCRhigh and TCRlow cells (10% of total cells for each condition) from specific MART-1/Melan-A (M26) and gp-100 (GP154) cytolytic T-lymphocytes (CTL) clones. Cytotoxicity assays were performed with human TAP-deficient T2 cells pulsed with increasing concentrations of peptide (M26: ELAGIGILTV and G154: KTWGQYWQV). We found that TCRlow CTL cannot kill target cells as efficiently as TCRhigh cells only in conditions of low pMHC complexes (i.e. 10-13 M peptide). Our results demonstrate that target cells with low pMHC complexes can evade TCRlow-mediated T-cell killing, whereas TCRhigh cells can kill efficiently at the same MHC conditions. We conclude that MHClow target cells can escape only from TCRlow lymphocyte attack and that this escape could be counter-balanced by increasing TCR densities in CTLs.