CD8+ T Cells Specific for ImmunodominantTrans-Sialidase Epitopes Contribute to Control ofTrypanosoma cruziInfection but Are Not Required for Resistance

Abstract

CD8+ T cells are essential for controlling Trypanosoma cruzi infection. During Brazil strain infection, C57BL/6 mice expand parasite-specific CD8+ T cells recognizing the dominant TSKB20 (ANYKFTLV) and subdominant TSKB74 (VNYDFTLV) trans-sialidase gene (TS)-encoded epitopes with up to 40% of all CD8+ T cells specific for these epitopes. Although this is one of the largest immunodominant T cell responses described for any infection, most mice fail to clear T. cruzi and subsequently develop chronic disease. To determine if immunodominant TS-specific CD8+ T cells are necessary for resistance to infection, we epitope-tolerized mice by high-dose i.v. injections of TSKB20 or TSKB74 peptides. Tolerance induction led to deletion of TS-specific CD8+ T cells but did not prevent the expansion of other effector CD8+ T cell populations. Mice tolerized against either TSKB20 or TSKB74, or both epitopes simultaneously, exhibited transient increases in parasite loads, although ultimately they controlled the acute infection. Furthermore, BALB/c mice tolerized against the TSKD14 peptide effectively controlled acute T. cruzi infection. These data are consistent with the hypothesis that development of high-frequency CD8+ T cell populations focused on TS-derived epitopes contributes to optimal control of acute infection but is not required for the development of immune resistance.

Inhibitory Receptor Expression on CD8+ T Cells Is Linked to Functional Responses against Trypanosoma cruzi Antigens in Chronic Chagasic Patients

“…), and parasitic (Toxoplasma gondii and Trypanosoma cruzi) infections, there is a delay in the generation of the CD8 + T cell immune response. In addition, Ag-specific T cells become dysfunctional, express inhibitory receptors, and even fail to control the infection (57)(58)(59)(60)(61)(62)(63)(64). Although this process was initially described for models of chronic viral infections, such as lymphocytic choriomeningitis, HIV, simian immunodeficiency, and HBV and HCV (12), recent studies have shown that this phenomenon also occurs in protozoan infections (65,66).…”

Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8+T Cells with Different Specificities

“…In a previous study, Rosenberg et al utilized a highdose peptide tolerization approach to specifically suppress the induction of CD8 ϩ T cells of defined specificity during Trypanosoma infection (31). Mice tolerized against two immunodominant epitopes experienced a transient increase in parasite load, indicating that the protective CD8 ϩ T cell response was weakened.…”

Advances and challenges towards a vaccine against Chagas disease

“…50 Importantly, mice tolerized for these dominant epitopes are still able to control acute T. cruzi infection through the activation of CD8 + T cells specific for unknown alternate epitopes. 51 Identifying these epitopes may thus lead to additional vaccine antigens that could complement trans-sialidase proteins.…”