Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis.

Luciana P Covre,Emma S Chambers,Herbert L De Matos Guedes,Reynaldo Dietze,Juliana A Silva,Arne N Akbar,Oliver P Devine,Daniel C O Gomes,Rodrigo R Rodrigues,Régia F Martins,Milica Vukmanovic-Stejic,Aloísio Falqueto

doi:10.3389/fimmu.2018.03001

Abstract

Leishmania (Viannia) braziliensis induces American tegumentary leishmaniasis that ranges in severity from the milder form, cutaneous (CL) to severe disseminated cutaneous leishmaniasis. Patients with CL develop a cell-mediated Th1 immune response accompanied by production of inflammatory cytokines, which contribute to parasite control and pathogenesis of disease. Here, we describe the accumulation of circulating T cells with multiple features of telomere dependent-senescence including elevated expression of CD57, KLRG-1, and γH2AX that have short telomeres and low hTERT expression during cutaneous L. braziliensis infection. This expanded population of T cells was found within the CD45RA+CD27− (EMRA) subset and produced high levels of inflammatory cytokines, analogous to the senescence-associated secretory profile (SASP) that has been described in senescent non-lymphoid cells. There was a significant correlation between the accumulation of these cells and the extent of systemic inflammation, suggesting that they are involved in the inflammatory response in this disease. Furthermore, these cells expressed high level of the skin homing receptor CLA and there was a highly significant correlation between the number of these cells in the circulation and the size of the Leishmania-induced lesions in the skin. Collectively our results suggest that extensive activation during the early stages of leishmaniasis drives the senescence of T cells with the propensity to home to the skin. The senescence-related inflammatory cytokine secretion by these cells may control the infection but also contribute to the immunopathology in the disease.

Highlights

Parasites belonging to the Leishmania genus are among of the most diverse human pathogens in terms of both geographical distribution and clinical manifestations
We observed increased frequencies of the cells surface senescence associated markers CD57 in CD4+ and CD8+ T cells (Figure 1A) and the inhibitory killer cell lectin-like receptor G1 (KLRG1) in CD8+ T cells in cutaneous leishmaniasis (CL) patients compared to controls (Figure 1B)
As senescent T cells that accumulated in CL patients were proinflammatory, especially after stimulation with L. braziliensis antigens, we investigated if they were associated with the skin immunopathology that occurs during the infection

Summary

Introduction

Parasites belonging to the Leishmania genus are among of the most diverse human pathogens in terms of both geographical distribution and clinical manifestations. T Cell Senescence in CL ranges from a localized cutaneous to a fatal visceral form, depending on parasite species and host immunity [1]. Parasites from the Viannia subgenus that include Leishmania (Viannia) braziliensis are the most widespread species in the Americas, causing cutaneous leishmaniasis (CL) [1]. The development of cutaneous lesions during CL is prevalent in more than 90% of cases and is characterized by an intense local cell-mediated Th1 immune response and production of inflammatory cytokines, which contribute to parasite control and tissue damage [2, 3]. Increased production of pro-inflammatory mediators, such as TNF-α, C-reactive protein (CRP), and adenosine deaminase (ADA) are observed in patients infected with Leishmania and may play an important role in the pathogenesis of disease [4, 5]

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Results

Conclusion