The immune system is continually challenged to mount productive responses to effectively clear infections. We aim to monitor the quality of responses by examining cells specific for challenging antigens on the single-cell mass spectrometric (CyTOF) in-depth platform. In particular, we studied responses to the seasonal influenza vaccine. Using our combinatorial tetramer staining strategy with 34 influenza class II MHC epitopes, we have obtained intriguing evidence for a direct correlation between robust CD4+ T cell responses with a follicular helper-like phenotype to particular antigens and elevated serological responses to an inactivated influenza vaccine. We also found that the magnitude of the specific CD4+ T cell response correlates with the flu-specific CD8+ T cell responses. Importantly, we have found that responses are widely varied amongst epitopes with this diversity not encompassed with just a few tetramers. As such the strength of this technique allows survey of the full immune response, of both class I and II simultaneously. The multiplexing strengths of mass cytometry combined with identification of antigen-specific T cells enables the detailed analysis of many varied immune responses, promoting future evaluations of vaccine efficacy, disease susceptibility and therapeutic success.