The pathogenesis of acute rheumatic fever (ARF) is poorly understood, limiting the development of immune-modulating therapies to treat disease and prevent progressive heart damage. Here, participants with definite ARF were compared to other severe acute paediatric conditions and matched healthy controls by profiling circulating immune molecules and cells to inform disease mechanisms and potential druggable pathways. ARF shared immunological similarities with other inflammatory conditions, including elevated serum IL-6 and an increased frequency of circulating CD4 T cells. However, elevation of the chemokine CCL5 and immunoglobulin IgG3, along with reduced expression of the chemokine receptor CXCR3 in the T cell compartment distinguished ARF from all other groups. Immunofluorescence imaging of rheumatic valve tissue confirmed a role for CXCR3-mediated T cell tissue homing during inflammatory disease. Together with a reduced frequency of circulating regulatory T cells, these data underscore a perturbed T cell compartment and provide a rationale for exploring currently available immune-modulating therapies to treat ARF.