Understanding CD8+ T Cell Immunity to Trypanosoma cruzi and How to Improve It

Abstract

The protozoan Trypanosoma cruzi is the causative agent of Chagas' disease, endemic in Latin America but present worldwide. Research efforts have focused on the examination of immune mechanisms that mediate host protection as well as immunopathology during this parasitic infection. The study of CD8⁺ T cell immunity emerges as a key aspect given the critical importance of parasite-specific CD8⁺ T cells for host resistance throughout the infection. In recent years, new research has shed light on novel pathways that modulate the induction, maintenance, and regulation of CD8⁺ T cell responses to T. cruzi. This new knowledge is setting the ground for future vaccines and/or immunotherapies. Herein, we critically review and analyze the latest results published in the field.

Keywords: CD8(+) T cells; Chagas' disease; Trypanosoma cruzi.

Figure 1, Key Figure.. Priming and maintenance of T. cruzi CD8⁺ T cell response.

a) T. cruzi infects different cell types within the host but at least one round of parasite replication is necessary to allow the accumulation of sufficient amounts of parasite antigens (Ags) and ligands able to activate antigen presenting cells with T cell priming ability. Dendritic cells (DC) recognize T. cruzi through ligation of toll-like receptors (TLR) that are nevertheless not essential for CD8⁺ T cell priming. Alternatively, Nod-like receptors (NLR) or bradykinin 2 receptors (B2R) may be involved in this process. b) Activated DCs prime naïve CD8⁺ T cells (T_N) that recognizes immunodominant as well as subdominant parasite epitopes. CD4⁺ T cell help seems to be mainly required in the induction of CD8⁺ T cells specific for immunodominant peptides. c) Upon priming, there is a robust expansion of parasite-specific effector CD8⁺ T cells (T_E) that show polyfunctional effector response and are critical for the control of parasite replication. T_E CD8⁺ T cell survival and effector function is sustained by particular cytokines and soluble mediators produced by different cell subsets. d) After the limitation of parasite burden, the CD8⁺ T cell response contracts and gives rise to effector memory (T_EM) and central memory (T_CM) CD8⁺ T cells that persist during the chronic phase. e) Although memory CD8⁺ T cells remains functional to limit parasite outgrowth, at least two scenarios have been reported in the chronic phase in relation to CD8⁺ T cell phenotype and functional competence.

Figure 2.. Pathways of CD8⁺ T cell suppression during T. cruzi infection.

T. cruzi infection induces the secretion of soluble anti- and pro-inflammatory mediators by a wide range of immune cell populations as well as the upregulation of inhibitory receptors, such as CTLA-4, by Treg cells. In turn, each mediator may target one or several functional mechanisms of the CD8⁺ T cell response, either acting directly on CD8⁺ T cells or indirectly through other cell subtypes. Concurrently, each aspect of the CD8⁺ T cell effector response might be controlled by more than one inhibitory mechanism. Suppression pathways are represented by different colors that show correspondence with the color of the arrow next to the CD8⁺ T cell process that they suppress (i.e proliferation, effector cytokine production or cytotoxicity). Solid lines indicate a demonstrated mechanism, while dashed lines illustrate possible interactions; arrow heads stand for activation/production while blunt ends denote inhibition/suppression. Treg cell, CD4⁺ Foxp3⁺ regulatory T cell; Tr1 cell, CD4⁺ Foxp3- IL-10⁺ regulatory T cell; DC, dendritic cell; MDSC, myeloid derived suppressor cell; NO, Nitric Oxide; CTLA-4, Cytotoxic T-Lymphocyte Antigen 4; TGF-b, transforming growth factor beta; IL, interleukin; TCR, T cell receptor.