Longitudinal tracking of immune responses against SARS-CoV-2 can provide insight into mechanisms of immune dysfunction in COVID-19. Mathew et al. carried out deep profiling of the T cell and B cell compartments in peripheral blood of patients with COVID-19, convalescent donors and healthy controls, using high-dimensional cytometry and multiplexed cytokine analyses. By overlaying immune and clinical features, the study identifies temporal patterns in populations of activated plasmablasts, effector memory T cells and CD4+ follicular T cells. Unsupervised cluster projection identifies three ‘immunotypes’ with distinct COVID-19 severity outcomes. Notably, one subgroup has CD4+ T cell and plasmablast activation associated with severe COVID-19; another subgroup has minimal or no lymphocyte response. This study underscores the various immune trajectories in COVID-19 and may explain differences in the response to immunosuppression.