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.

Persistent T cell unresponsiveness associated with chronic visceral leishmaniasis in HIV-coinfected patients

“…More in-depth studies targeting other markers of cellular senescence, such as telomere length, are crucial to discriminate between reversible T cell exhaustion and irreversible T cell senescence processes, to disentangle the pathways for future immunotherapeutic approaches. For instance, the high T cell exhaustion levels could be reversed with TIGIT/PD-1 co-blockade using the currently approved immune checkpoint inhibitors in cancer research 4,50 . Especially in di cult-to-cure VL-HIV patients, the associated high toxicity and variable cure rates with such immune checkpoint inhibitors may be within the acceptable range 51 .…”

An integrated analysis of the structural changes and gene expression of spleen in human visceral leishmaniasis with and without HIV coinfection

“…This gene was found to induce B cell differentiation into plasma cell, to be highly expressed in T cell exhaustion and to induce regulatory FOXP3+ T cell to secrete IL10 (33,34). T cell exhaustion is a condition that has been associated with the progression of VL and spleen disorganization (28,35,36), particularly in patients with HIV co-infection (4). The patients with VL of this study showed high expression levels of PRDM1 , CD274 ( PD-L1 ), and CD44 , which also supports the hypothesis of T cell exhaustion.…”

COVID-19 and Diarylamidines: The Parasitic Connection

“…In addition, a recent report showed that a 4th booster shot resulted in significant IgG4 subtype elevations [ 124 ], consistent with immunosuppression, potentially predisposing individuals to other diseases. Host immunosuppression (T-cell exhaustion and chronic disease) resulting from protozoa or multiple SARS-CoV-2 variant infections is now well documented [ 125 , 126 , 127 ]. Thus, alternative treatments such as localized mucosal and oral-based vaccines [ 128 ], antivirals [ 129 ], and broad-based antiparasitics or combinations thereof are being considered.…”