Invariant natural killer cells (iNKTs) are a specialized subset of T cells that get activated by immunostimulatory lipids presented on CD1d immunoreceptors. Once activated, iNKTs mount a myriad of immune responses, ranging from Th1, Th2, Th17, Treg, or TFH-like, depending on the chemistry and structure of the presented lipid. The robust and rapid response orchestrated by iNKTs is not only critical to biology, but also to the development of next-generation immunotherapies and vaccine adjuvants. However, the ability to engineer fine-tuned CD1-mediated lipid immune responses for specific purposes remains limited due to a lack of fundamental mechanisms underpinning the process. Molecular dynamics simulations and crystal structures of CD1d:lipid:TCR complexes provide evidence that lipid/CD1 complex stability, interaction kinetics, lipid head group chemistry, and conformational changes in CD1 or TCR proteins may be involved. Yet, structural insights into these interactions in solution are still missing. Here, specialized isotopic labeling schemes and high field solution NMR spectroscopy are applied to decipher the biomolecular interactions between iNKT TCRs and lipid/CD1d complexes with distinct immunological outcomes. Dynamic features and conformational changes responsible for unique immunosignaling outcomes are also probed within picosecond to nanosecond and microsecond to millisecond timescales. Together, our results provide new insights into the interactions of iNKT TCRs with CD1:lipid complexes in solution.