T Lymphocyte Exhaustion During Human and Experimental Visceral Leishmaniasis

Abstract

A key point of immunity against protozoan Leishmania parasites is the development of an optimal T cell response, which includes a low apoptotic rate, high proliferative activity and polyfunctionality. During acute infection, antigen-specific T cells recognize the pathogen resulting in pathogen control but not elimination, promoting the development and the maintenance of a population of circulating effector cells that mount rapid response quickly after re-exposure to the parasite. However, in the case of visceral disease, the functionality of specific T cells is lost during chronic infection, resulting in inferior effector functions, poor response to specific restimulation, and suboptimal homeostatic proliferation, a term referred to as T cell exhaustion. Multiple factors, including parasite load, infection duration and host immunity, affect T lymphocyte exhaustion. These factors contribute to antigen persistence by promoting inhibitory receptor expression and sustained production of soluble mediators, influencing suppressive cell function and the release of endogenous molecules into chronically inflamed tissue. Together, these signals encourage several changes, reprogramming cells into a quiescent state, which reflects disease progression to more severe forms, and development of acquired resistance to conventional drugs to treat the disease. These points are discussed in this review.

Keywords: T cell exhaustion; Th subsets; inflammation; inhibitory receptor; visceral leishmanaisis.

Figure 1

T cell response after viscerotropic leishmania parasites recognition. When L. donovani or L. infantum antigens are recognized, specific naïve CD4⁺ T cells (blue cells) are activated and differentiate into distinct subtypes of T helper lymphocytes (Th1, Th17 – green cells), restricting the parasites replication. After parasite declining, the most of Th cells die and the remaining cells differentiate into memory T cells (yellow cells). In the case of secondary exposure to the microorganism, memory T cells may be reactivated and promoting parasite control (A). Situations where the specific immune response generated in the host cannot control the parasite, a chronic infection process is established. The parasite’s persistence induces Thelper cells to enter a non-functional state, a term referred as exhaustion (represented by orange cells), rather than developing a classical memory cells. Exhausted T cells present a compromised effector functions and maintain the persistence of the parasites in the host for long periods, which reflects disease progression to more severe forms, but it was not found it in asymptomatic individual or patients with mild form of disease (B). Created with BioRender.com (Agreement number: IK23QKCBAC).

Figure 2

T cell fate during Visceral Leishmaniasis. During infection with L. donovani or L. infantum, monocyte-derived cell (i.e. dendritic cell or macrophage) (purple cells) produce pro-inflammatory cytokines (IL-1β, IL-6, IL-12 and IL-23), which act on naive T lymphocytes, targeting the cells to Th1 and Th17 subtypes (green cells), resulting in the production of IFN-γ/IL-17 (A). Secreted IFN-γ and IL-17 promote the phagocytes microbicidal function of monocyte-derived cell trough the release of ROS and NO, reducing the parasite load (B). The persistent presence of parasites induces a sustained and maintained production of regulatory molecules, such as TGF-β, IL-10, IL-27, PGE2, which promote exhaustion of T lymphocytes (yellow cells), a process characterized by increased expression of inhibitory molecules, such as CTLA-4, PD-1, TIM3, TIGIT, CD39, CD73, LAG-3, on T cell surface. As a consequence, the proliferative response and production of pro-inflammatory cytokines are suboptimal, mechanisms by which the parasite uses to survive in the host-vertebrate (C). Such regulatory molecules influence the inhibitory receptors on the surface of Treg cells (red cells) impacting on their both differentiation and suppressive function (D) and upon DCs functions (F). Such factors repress the protective immune response mediated by IFN-γ/IL-17 and ROS/NO (G). Tregs also respond to regulatory molecules, and contribute to the exhaustion process of T lymphocytes by sustaining the release of regulatory mediators (TGF-β, IL-10, IL-35, PGE2 and adenosine) in the microenvironment and maintaining high levels of inhibitory molecules on the surface of exhausted T lymphocytes (E). Together, these signs favor the persistence of the parasite. Legends: green arrow (induction of effector response), red arrow (induction of suppressor response), red dotted arrow (inhibition of effector response). Created with BioRender.com (Agreement number: LC23QKDV88).