The cell-mediated immune response is the branch of the adaptive immune system responsible for recognizing and destroying infected cells. T lymphocytes express the surface protein T cell receptor (TCR) which interacts with a Major Histocompatibility Complex (MHC) presenting a peptide on the surface of antigen presenting cells. While TCRs display a level of cross reactivity to ensure adequate coverage of peptide/MHC (pMHC), they are also restricted to recognizing epitopes within the context of an MHC. This so-called MHC bias has been studied for decades, with many theories emerging as to why TCRs might display such blatant favoritism. While structures of TCR-pMHC complexes have failed to identify any conserved interactions between TCR and MHC [1], the existence of coreceptor-independent TCR-pMHC interactions muddles their role in imparting MHC bias for proper signaling [2]. What has become clear is that the original "rules of engagement" for TCR-pMHC interactions are evolving as new biophysical, structural, and immunological data becomes available. To this end, we have taken some of the core ideas about TCR-pMHC interactions and studied them further. Up until recently, all evidence pointing towards conserved TCR-MHC interactions was based on structural study. We decided to look from a different perspective by studying the sequence information for CDR loops of T cell receptors. This yielded tremendous insight and confirmed that TCR interfaces are largely unique yet contain enrichment for specific charged residues that may facilitate binding to particular HLA alleles. We have also explored the roles that a single conserved TCR residue might have for pMHC recognition. While being important for proper recognition of pMHC, both structural and fluorescence anisotropy data suggests this residue may be exerting its influence by maintaining the CDR loop conformations or flexibility necessary for recognition. Other areas, such as immunological or genetic roles might also explain its conservation. These results paint a more complex picture of TCR-pMHC interactions than was originally hypothesized to exist. Still, most of the findings make sense in biochemical and biophysical terms, highlighting a need for more experimentation in these fields to truly understand the functioning of the adaptive immune system.1. Marrack, P., et al., Evolutionarily conserved amino acids in TCR V regions and MHC control their interaction. Annual review of immunology, 2008. 26: p. 1712. Kerry, S.E., et al., Interplay between TCR Affinity and Necessity of Coreceptor Ligation: High-Affinity Peptide-MHC/TCR Interaction Overcomes Lack of CD8 Engagement. The Journal of Immunology, 2003. 171(9): p. 4493-4503