Interactions with multiple peptide ligands determine the fate of developing thymocytes

Abstract

Thymocytes are positively or negatively selected depending on interactions between their T cell receptors (TCR) and peptides presented by major histocompatibility complex molecules. We have previously shown that apoptosis of thymocytes from an ␣␤ TCR-transgenic mouse (F5), induced by antigenic peptide, can be inhibited specifically by an antagonist peptide variant in an in vitro culture model. We have now extended these experiments by demonstrating that the antagonist peptide can inhibit natural negative selection of maturing thymocytes, induced by endogenously expressed antigen, in fetal thymic organ cultures (FTOC). This inhibition resulted in the rescue and maturation of thymocytes that would otherwise have been deleted. Mature T cells generated in these cultures were able to respond to antigen by producing limited quantities of interferon-␥, but unlike T cells from control FTOC, they required exogenous interleukin-2 to generate cytolytic effector cells. Interestingly, the antagonist peptide also accelerated the development of F5 thymocytes in the absence of the negatively selecting ligand. These data suggest that the developmental fate of a thymocyte may be determined by the recognition of multiple distinct peptide ligands during thymic selection. Alterations in the profiles of selecting peptides presented in the thymus would thus have profound effects on the size and autoreactive potential of the T cell repertoire generated.T lymphocytes are positively or negatively selected in the thymus as a result of interactions between their T cell receptors (TCR) and thymic peptide-major histocompatibility complexes (MHC) (1-11). Much of the recent work on thymic selection was influenced by experiments that examined T cell responses to peptide analogs, produced from the antigenic peptide by substitution of amino acid residues involved in interaction with the TCR. Such peptide analogs can generate qualitatively different T cell responses compared with those produced by the antigenic peptide (12). In particular, some analogs were shown to act as TCR antagonists and inhibit T cell responses to the antigenic peptide (13). Several studies have shown that antagonist peptides are capable of positively selecting (9, 10), negatively selecting (14, 15), or blocking positive selection (16) of thymocytes. However, other studies have found that the ability of a peptide to select thymocytes positively or negatively does not always correlate with its properties as a TCR antagonist (10,11,17,18).We have previously reported an analog peptide (19) that was capable of inhibiting antigen-specific lysis of target cells by cytotoxic T lymphocyte (CTL) from ␣␤ TCR (F5)-transgenic mice (20,21). Furthermore, this peptide was shown to inhibit apoptosis of transgenic thymocytes (19) in an in vitro suspension culture assay (22). Because the suspension culture could not support the development of immature thymocytes, we could not determine whether this inhibition would result in the rescue and complete maturation of thymocytes. In the pre...

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