The immune system is vitally important for resolving COVID-19 when individuals are infected with the SARS-CoV-2 virus. Moreover, the vaccines that are being administered to millions of people across the globe are designed to “pre-warn and arm” the immune system so that if infected with SARS-CoV-2, individuals are significantly less likely to develop severe disease or die. Here, two crucial arms of the immune system, namely B cells and T cells, play a central role. While we have a molecular understanding of how antibodies, which are produced by B cells, can bind and neutralize the spike protein from SARS-CoV-2, up until now researchers did not know how T cell receptors (TCRs), which are found on T cells, recognize antigens that arise from the spike protein. “T cells play an important role in immunity against both SARS-CoV-2 vaccination and severe acute respiratory infection,” said University of Melbourne professor Katherine Kedzierska, a laboratory head at the Peter Doherty Institute for Infection and Immunity. “Although T cells in COVID-19 have been studied previously, the molecular basis underpinning TCR recognition of SARS-CoV-2 remained unknown.” In a world first finding, co-led by and Kedzierska, and Monash University’s Dr. Priyanka Chaurasia, Dr. Jan Petersen, and professor Jamie Rossjohn, the team analysed the TCR recognition of a spike protein fragment when presented by an immune molecule, termed Human Leukocyte Antigen A2 (HLA-A2). This work, which utilized the Australian Synchrotron, was published in the Journal of Biological Chemistry. “This is a piece of a larger puzzle. While SARS-CoV-2 continues to evolve, we have to build our understanding of how effective immune responses work,” said Petersen. The team provided important molecular insight into understanding how T cells of the human immune system respond to SARS-CoV-2. Different individuals mount differing immune responses to SARS-CoV-2, and this work provided fundamental insight into such an immune response.