DUAL T-CELL RECEPTOR T-CELLS HAVE A DECREASED SENSITIVITY TO PHYSIOLOGICAL LIGANDS DUE TO REDUCED DENSITY OF EACH T-CELL RECEPTOR

A considerable fraction of T cells express two distinct T cell recepto rs (TCR), mainly due to expression of two TCR alpha chains. It has bee n suggested that such dual-TCR cells could have a role in autoimmunity . However, as such cells express less of each TCR, they could be less sensitive to their physiological ligand, i.e. peptide plus major histo compatibility complex molecules (MHC). We tested this hypothesis in a transgenic TCR model in which most T cells express different amounts o f the transgene-encoded TCR due to expression of endogenous TCR alpha chains. Five Th1 clones derived from lambda 2(315) immunoglobulin ligh t chain-specific TCR-transgenic mice expressed different levels of the transgene-encoded TCR, ranging from similar to 10 000 to similar to 5 0 000 TCR per cell. Cytosolic Ca2+ mobilization in single T cells from these dones elicited by lambda 2(315) peptide-pulsed, I-E(d)-expressi ng antigen-presenting cells, correlated linearly with the relative tra nsgene-encoded TCR expression. The peptide requirement for half-maxima l T cell proliferation showed a similar correlation, with low TCR leve ls requiring higher peptide concentration. Corroborative evidence was obtained by deployment of short-term polyclonal CD4(+) lines from TCR- transgenic mice. Such lines had reduced early (Ca2+ mobilization) and late (lymphokine and proliferation) responses, compared with T cell li nes from recombination-deficient TCR-transgenic severe combined immuno deficiency mice (which express only a single transgene-encoded TCR). T aken together, the Ca2+ responses increase gradually with increasing T CR expression per cell, similar to the previously described analog Ca2 + signaling elicited by increasing amounts of peptide/MHC [Rotnes et a l., Eur. J. Immunol. 1994. 24: 851]. Surprisingly small reductions in TCR expression per cell reduce T cell responsiveness. This suggests th at dual-TCR T cells are immunologically less effective than single-TCR T cells.