UCSF

The immune system persists in a sensitive equilibrium, necessarily avoiding overreaction to illegitimate threats while watchfully waiting for any bona fide harms that might come along. Fortunately, myriad cell extrinsic and intrinsic mechanisms have evolved to fortify this steady state. Amongst these regulatory forces, three distinct yet interdependent signals lie at the heart of immune activation. This first signal – engagement of the B or T cell receptor by cognate antigen – has significant diagnostic and therapeutic potential. After the emergence of SARS-CoV-2 and its associated clinical syndrome, COVID-19, we led a nationwide, multi-disciplinary scientific and clinical team to systematically benchmark numerous serological assays testing for effective “signal 1” responsiveness to SARS-CoV-2-associated antigens. Establishing accuracy of these tests had significant implications on governmental policies relating to the pandemic, as well as efforts to employ these serology tests to understand COVID-19 seroprevalence and protective immunity. Next, we applied computational tools to improve the performance of these serological tests through combinatorial application and companion analyses. Lastly, we followed these studies of serology diagnostics (corresponding to signal 1) with systematic molecular studies of costimulation: the second signal influencing T cell activation. This critical next step is indispensable to immune responsiveness, but the intricacies of regulatory factors influencing each step have yet to be systematically studied. Our labs have pioneered the use of functional genomic screening using CRISPR/Cas9 to thoroughly explore the regulatory landscape of various immunological phenotypes. Thus, we leveraged recent molecular advances to functionally define the cis and trans regulators converging on the human costimulatory locus harboring CD28, CTLA4, and ICOS at scale. This work uncovered gene-, cell subset-, and stimulation-specific cis-regulatory elements (CREs) bound by validated trans regulators to influence costimulatory gene expression. Finally, deep characterization of genomic architecture in the locus defined critical insulator elements reinforcing CRE activation of true targets while also preventing spurious activation of flanking genes. Ultimately, similar demonstrations of collaborative science to study the human immune system whether in the form of fundamental genomic immunology or translational immune diagnostics will aid our collective transition to the next generation of more precise biomedicine.