CD8+ T-Cells Expressing Interferon Gamma or Perforin Play Antagonistic Roles in Heart Injury in Experimental Trypanosoma Cruzi-Elicited Cardiomyopathy

Abstract

In Chagas disease, CD8+ T-cells are critical for the control of Trypanosoma cruzi during acute infection. Conversely, CD8+ T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC). Here we explored the role of CD8+ T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain. Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection. Further, there was no association between heart injury and systemic anti-T. cruzi CD8+ T-cell capacity to produce interferon-gamma (IFNγ) and to perform specific cytotoxicity. Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue. In T. cruzi infection, most of the CD8+ T-cells segregated into IFNγ+ perforin (Pfn)neg or IFNγnegPfn+ cell populations. Colonization of the cardiac tissue by anti-T. cruzi CD8+Pfn+ cells paralleled the worsening of CCC. The adoptive cell transfer to T. cruzi-infected cd8 −/− recipients showed that the CD8+ cells from infected ifnγ−/− pfn +/+ donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8+ cells from ifnγ +/+ pfn −/− donors. Moreover, the reconstitution of naïve cd8 −/− mice with CD8+ cells from naïve ifnγ +/+ pfn −/− donors ameliorated T. cruzi-elicited heart injury paralleled IFNγ+ cells accumulation, whereas reconstitution with CD8+ cells from naïve ifnγ −/− pfn +/+ donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn+ cells in the cardiac tissue. Our data support a possible antagonist effect of CD8+Pfn+ and CD8+IFNγ+ cells during CCC. CD8+IFNγ+ cells may exert a beneficial role, whereas CD8+Pfn+ may play a detrimental role in T. cruzi-elicited heart injury.

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

“…Specific mechanisms regulating the effects of T cells in the heart during MAV-1 myocarditis have not yet been defined. CD8 ϩ T cells may play both inflammatory and cytolytic roles during infection, either by secretion of cytokines, such as IFN-␥ or TNF-␣, or through release of cytolytic granules such as Pfn (41). Both type I and type II IFN can play protective roles in other models of viral myocarditis (12)(13)(14).…”

“…Both type I and type II IFN can play protective roles in other models of viral myocarditis (12)(13)(14). IFN-␥ and Pfn play antagonistic roles during chronic myocarditis caused by Trypanosoma cruzi, with Pfn ϩ CD8 ϩ T cells implicated in causing tissue damage and IFN-␥ ϩ CD8 ϩ T cells preventing tissue damage (41). In the current study, we identified robust induction of IFN-␥ in the heart after MAV-1 infection, consistent with previous studies showing induction of IFN-␥ in MAV-1-infected lungs (25,26).…”

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

“…Studies have shown that the severity of the disease, that is, tissue damage, resulting from Leishmania braziliensis infection is directly correlated with more granzymeproducing CD8 + T cells (76) and that CD8 + T cell-mediated cytotoxicity promotes lesions in cutaneous leishmaniasis (77). In addition, CD8 + T cells producing perforin might play a detrimental role in experimental T. cruzi infection in mice, leading to heart injury (78). Hence the infection severity in CCP might be associated with the increased frequency of CD8 + T cells with potent cytotoxic profiles corroborated by the high amount of granzyme B produced by the CD8 + T cells from patients classified as group D (Supplemental Fig.…”

CD8+T Cell-Mediated Immunity duringTrypanosoma cruziInfection: A Path for Vaccine Development?

“…These lymphocytes produce perforin, but not IFN- γ , and have a greater propensity to migrate to the heart tissue, causing tissue damage leading to CCC [85]. …”