Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8⁺T Cells

Abstract

c Trypanosoma cruzi infection drives the expansion of remarkably focused CD8؉ T cell responses targeting epitopes encoded by variant trans-sialidase (TS) genes. Infection of C57BL/6 mice with T. cruzi results in up to 40% of all CD8 ؉ T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clear T. cruzi infection and subsequently develop chronic disease. One possible reason for the failure to cure T. cruzi infection is that immunodomination by these TS-specific T cells may interfere with alternative CD8 ؉ T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlled T. cruzi infection and developed effector CD8 ؉ T cells that maintained an activated phenotype. Memory CD8 ؉ T cells from drug-cured TSKB-transgenic mice rapidly responded to secondary T. cruzi infection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8؉ T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to control T. cruzi infection. These data also indicate that the relative position of an epitope within a CD8؉ immunodominance hierarchy does not predict its importance in pathogen control.

Combination of Mycobacterium indicus pranii and Heat-Induced Promastigotes Cures Drug-Resistant Leishmania Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells

“…We observed an expected increase of the CD44 hi CD11a hi population of CD4 ϩ T cells (1.4-fold; P Ͻ 0.001 versus uninfected animals) and of CD8 ϩ T cells (2.2-fold; P Ͻ 0.05 versus uninfected animals) in infection ( Fig. 3C, D, and H; Table S2E) (22,23). However, the therapy enhanced the proliferation in spleen of the CD44 hi CD11a hi population of CD4 ϩ T cells (1.7-fold, P Ͻ 0.001; versus infected animals) over CD8 ϩ T cells (1.5-fold, P Ͻ 0.05; versus infected animals) ( Fig.…”

“…CD11a expression is also essential for the development and maintenance of the tissue specific memory T lymphocytes (21). CD44 hi CD11a hi marks the population of antigen-experienced T cells (22,23). We observed an expected increase of the CD44 hi CD11a hi population of CD4 ϩ T cells (1.4-fold; P Ͻ 0.001 versus uninfected animals) and of CD8 ϩ T cells (2.2-fold; P Ͻ 0.05 versus uninfected animals) in infection ( Fig.…”

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

“…A number of factors may impinge on the quality and magnitude of the T‐cell response, including parasite‐driven immature thymocyte apoptosis 105 and direct and indirect modulation of DC‐T cell interactions 106‐109 . In terms of antigen specificity, the murine T‐cell repertoire is focussed mainly on a small number of immunodominant epitopes from highly expressed surface proteins, 110‐112 but in humans there is evidence of a broader hierarchy 97,113 and immunodominance appears not to directly contribute to chronicity.…”

“…Signatures of strong positive selection in surface gene families 181 indicate immune pressure for diversification of antigens. At the population level, simultaneous expression of massively diverse ‘decoy’ antigens may conceivably prevent T‐ or B‐cell clones specific to any particular epitope from reaching sufficient frequency in infected tissues and/or effector capacity, 83,112,180,182 but direct evidence for this is lacking.…”

T Cell Specificity: A Great Challenge in Chagas Disease

“…Moreover, the CD8 + T cell response focused on a few epitopes (33,(59)(60)(61) was interpreted in favor of the hypothesis of immunodominance against certain peptides as mechanism to evade the immune response (62). Nonetheless, experimental approaches with mouse models later demonstrated that the immune control of T. cruzi infection was independent of the recognition of the therein called "dominant" TSKB20 and "subdominant" TSKB18 epitopes (58,63). In fact, despite the widespread idea of TS broad dominance of the T cell response against T. cruzi, there is insufficient evidence of a correlate in the context of human infection.…”