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

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.

Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8+ T cells in human cutaneous leishmaniasis

“…g). This suggests that the increased potential for skin homing through the higher expression of CLA leads to a preferential accumulation of senescent CD8 + T cells in the skin lesions of CL patients, which extends previous observations …”

“…c) had the largest cutaneous lesions (Fig. c), suggesting that they have a role in the cutaneous immunopathology, as was shown previously for senescent (EMRA, or effector memory T cells that re‐express CD45RA) CD8 + T cells in these patients . Furthermore, we found a significant correlation between the increase in senescent NK and senescent CD8 + T cells in the same patients (Fig.…”

“…CD8 T cells expressing higher levels of CLA are found in patients with cutaneous disorders including cutaneous leishmaniasis, compared with healthy individuals. This raises the question of how CLA expression is induced on these cells.…”

“…Alternatively, it is possible that specific CD8 + memory T lymphocytes are programmed to express CLA after antigenic stimulation. For example, the expression of CLA by memory CD8 + T lymphocytes increases during CL and is seen after Leishmania antigen recall in vitro . Furthermore, CLA‐negative precursor cells can be induced from CLA‐negative CD8 + T‐cell populations after TCR stimulation with viral and bacterial antigens .…”

“…In patients with CL, the accumulation of cytotoxic CD8 + T cells or granzyme B‐producing cells was linked with the severity of CL . We showed recently that CD8 + T cells are driven towards senescence acquiring high cytotoxic potential and skin‐homing capacity, which may promote skin damage . Although the role of cytotoxic and senescent CD8 + T cells in the immunopathology in CL is established, it is not clear if senescent natural killer (NK) cells also have a role in this process.…”