Blazing a trail in T-cell recognition.

Most T lymphocytes recognize peptide antigens presented by class I or class II molecules of the MHC. Hanada et al describe a novel TCR whose ligand contains no MHC molecule, but rather comprises soluble TRAIL (TNF-related apoptosis-inducing ligand) bound to Death Receptor 4 (DR4).1 T lymphocytes bearing heterodimeric TCRs, which are generated during thymic development by rearrangement of noncontiguous gene segments encoded in the T-cell receptor and loci, comprise the majority of T cells in blood and lymph nodes. Positive and negative selection of thymocytes bearing TCRs produces a naive T-cell repertoire that collectively expresses 2-3 106 distinct antigen receptors.2 The natural ligands for most TCRs (including those that participate in thymic selection) are short peptides bound to the antigen groove of the highly polymorphic class I and class II molecules of the MHC. In addition, small numbers of T cells expressing TCRs whose natural ligands are lipid molecules bound in the analogous antigen groove of monomorphic MHC class Ib molecules such as CD1 can be found in all individuals. Rare exceptions to the rule that T cells recognize small peptide or lipid moieties bound to the antigen groove of classic or nonclassical MHC molecules have been described. CD8 T-cell lines showing MHCunrestricted recognition of a tandemly repeated peptide epitope in the extracellular domain of the mucin molecule MUC1, a type I transmembrane protein, have been generated in vitro,3 and direct recognition of Hfe, a MHC class Ib molecule that does not have any antigen-presenting function, and its human orthologue HFE by murine CD8 T cells has also been described.4 In this issue of Blood, Hanada et al1 further expand the range of potential ligands for TCRs. Through sequential expression screening of cDNA libraries, they demonstrate that the TCR of a human CD4 T-cell clone recognizes a molecular complex that contains neither a small peptide, nor lipid moiety, nor protein product of the MHC, but rather soluble TRAIL bound to DR4 (see figure). Hanada et al had previously shown that this T-cell clone, isolated from an individual with renal cell carcinoma (RCC), displayed MHC-unrestricted recognition of a determinant expressed on most RCC lines, but not on EBV-transformed B cells or dermal fibroblasts derived from RCC patients.5 Transfection of the rearranged TCR and chain genes from the clone into allogeneic T cells was sufficient to transfer the MHC-unrestricted recognition of RCC cells, and a role for TRAIL in target cell recognition was suggested by the observation that recognition of RCC targets was inhibited by an anti-TRAIL antibody.5 In the current study, Hanada et al screened a cDNA expression library prepared from RCC cells and demonstrated that DR4 —also known as TRAIL-receptor 1—was a component of the molecular complex recognized by the RCC-specific T-cell clone, and that DR4 binding its natural ligand TRAIL was involved in target cell recognition. Additional cDNA expression screening revealed that the interaction of the RCC-specific TCR with the TRAIL/DR4 determinant on target cells was strongly enhanced by the interaction of CD2 on the T cells with its cognate ligand CD58 on target cells. Transfection assays revealed that expression of a CD58 cDNA and a truncated cDNA encoding only the membrane-bound extracellular portion of DR4 was sufficient for T-cell recognition, implying that signal transduction by DR4 in target cells was not required. The authors next tested the hypothesis Diversity of cell-surface ligands for TCRs. Professional illustration by Kenneth X. Probst.