Epitopes in the GPI attachment signal peptide of Trypanosoma cruzi mucin proteins generate robust but delayed and nonprotective CD8+ T cell responses

• Published in: The Journal of immunology (1950) Vol. 210; no. 4; pp. 420 - 430
• Main Authors: Bunkofske, Molly E., Perumal, Natasha, White, Brooke, Strauch, Eva-Maria, Tarleton, Rick
• Format: Journal Article
• Language: English
• Published: 15.02.2023
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2200723

Infection with the protozoan parasite Trypanosoma cruzi elicits substantial CD8 + T cell responses that disproportionately target epitopes encoded in the large trans-sialidase (TS) gene family. Within the C57BL/6 infection model, a significant proportion (30–40%) of the T. cruzi -specific CD8 + T cell response targets two immunodominant TS epitopes, TSKb18 and TSKb20. However, both TS-specific CD8 + T cell responses are dispensable for immune control and TS-based vaccines have no demonstrable impact on parasite persistence, a determinant of disease. Besides TS, the specificity and protective capacity of CD8 + T cells that mediate immune control of T. cruzi infection is unknown. With the goal of identifying alternative CD8 + T cell targets, we designed and screened a representative set of genome-wide, in-silico predicted epitopes. Our screen identified a novel T cell epitope MUCKb25, found within mucin family proteins, the 3 rd most expanded large gene family in T. cruzi . The MUCKb25-specific response was characterized by delayed kinetics, relative to TS-specific responses, and extensive cross-reactivity with a large number of endogenous epitope variants. Similar to TS-specific responses, the MUCKb25 response was dispensable for control of the infection and vaccination to generate MUCK-specific CD8 + T cells failed to confer protection. The lack of protection by MUCK vaccination was partly attributed to the fact that MUCKb25-specific T cells exhibit limited recognition of T. cruzi -infected host cells. Overall, these results indicate that the CD8 + T cell compartment in many T. cruzi -infected mice is occupied by cells with minimal apparent effector potential.