Little is known about the antigen specificity of CD1d-restricted T cells, except that they frequently recognize CD1d-expressing antigen-presenting cells in the absence of exogenous antigen. We previously demonstrated that the 24.8.A iNKT cell hybridoma was broadly reactive with CD1d-transfected cell lines and recognized the polar lipid fraction of a tumor cell extract. In the present study, the antigen recognized by the 24.8.A iNKT cell hybridoma was purified to homogeneity and identified as palmitoyl-oleoyl-sn-glycero-3-phosphoethanolamine (16:0 -18:1 PE). The 24.8.A iNKT cell hybridoma recognized synthetic 16:0-18:1[cis] PE, confirming that this phospholipid is antigenic. Recognition correlated with the degree of unsaturation of the acyl chains. Using a panel of synthetic PEs, the 24.8.A iNKT cell hybridoma was shown to be activated by PEs that contained at least one unsaturated acyl chain. The configuration of the double bonds was important, as the 24.8.A iNKT cell hybridoma recognized unsaturated acyl chains in the cis, but not the trans, configuration. PEs with multiple double bonds were recognized better than those with a single double bond, and increasing acyl chain unsaturation correlated with increased binding of PE to CD1d. These data illustrate the potential importance of the acyl chain structure for phospholipid antigen binding to CD1d.
Human and murine T cells that specifically recognize CD1d and produce IL-4 and IFN-γ play a role in immunoregulation and tumor rejection. In the mouse, most CD1d1-reactive T cells described express an invariant Vα14-Jα281 TCR associated with TCR β-chains of limited diversity. Similarly, human CD1d-reactive T cells express a highly restricted TCR repertoire. Here we report the unexpected result that in mice immunized with CD1d1-bearing transfectant cells, a diverse repertoire of TCRs was expressed by CD1d1-reactive T cell clones isolated by limiting dilution without preselection for NK1 expression. Only 3 of 10 CD1d1-reactive T cell clones expressed the invariant Vα14-Jα281 TCRα rearrangement. T cells expressing Vα10, -11, -15, and -17, and having non-germline-encoded nucleotides resulting in diverse V-J junctions were identified. Like CD1d1-reactive T cells expressing the invariant Vα14-Jα281 TCR α-chain, CD1d1-reactive clones with diverse TCRs produced both Type 1 (IFN-γ) and Type 2 (IL-4, IL-10) cytokines. This establishes the existence of significant diversity in the TCRs directly reactive to the CD1d1 protein. Our findings reveal that CD1d interacts with a broad array of TCRs, suggesting substantial redundancy and flexibility of the immune system in providing T cells serving the role(s) mediated by CD1d reactivity.
Objective. Previously, we showed that 15-20% of patients with rheumatoid arthritis (RA) have oligoclonal expansions of peripheral blood CDS+ T cells expressing T cell receptors encoded by the VJ2 (AV12S1) gene. To better understand the significance of these expansions, the present study was undertaken to determine their specificity.Methods. We cloned and characterized V,12+,CDS+ T cells from the peripheral blood of 1 RA patient with a clonal expansion of these T cells.Results. The T cell clones were autoreactive since they recognized autologous, but not allogeneic, antigenpresenting cells. Upon activation, these T cells secreted interleukin-4 and interleukin-10. The autoreactive T cell clones were class I major histocompatibility complex (MHC) restricted, by either HLA-B60 or HLA-Cw3. Since the original report from this laboratory of clonal and oligoclonal expansions of V,12+ (AV12Sl),CD8+ T cells in the blood and synovial tissue of patients with rheumatoid arthritis (RA) (l), subsequent reports have documented expansions of CD8+ T cells in both normal individuals and patients with a Conclusion. A large population of class I MHCrestricted CDS+ T cells in a patient
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