Highly cross-reactive and competent effectors dominate the CD8+ T cell response in Trypanosoma cruzi infection

CD8+ T cells are key effectors in immune control of Trypanosoma cruzi infection. Within C57BL/6 mice, the T. cruzi-specific CD8+ T cell response is largely comprised of T cells recognizing trans-sialidase (TS)- and mucin-encoded epitopes. Despite their immunodominance, these epitope-specific CD8+ T cells are entirely dispensable for immune control. In a screen for epitopes inducing "protective" CD8+ T cells, we uncovered a high level of cross-reactivity within the TSKb20-specific CD8+ T cell response. This cross-reactivity was driven by the TSKb20 epitope itself and not the infection. TCR sequencing defined key characteristics of the TSKb20 repertoire including biased TRBV12-1/12-2 and TRBJ2-1/2-7 gene usage and a highly dominant CDR3β motif. The dispensability of the TSKb20 response in the control of T. cruzi infection along with the broad reactivity of this T cell population prompted us to assess the relative effector capacity of TSKb20 T cells at the site of reinfection. Similar to other activated CD8+ T cells at the site, TSKb20-specific CD8+ T cells expressed transcriptional patterns associated with effector function, suggesting that TSKb20 T cells are capable and likely participants in parasite control. These results indicate that broad TCR reactivity does not compromise the ability of TSKb20-specific T cells to develop into phenotypically functional effectors. Additionally, the failure to identify individual parasite epitopes capable of driving a protective CD8+ T cell response challenges the paradigm that individual T. cruzi epitopes, including highly immunodominant ones, are critical to or exploitable for the potent recognition of T. cruzi-infected host cells and infection control.