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

Abstract

Summary Cytotoxic activity mediated by CD8+ T cells is the main signature of the immunopathogenesis of cutaneous leishmaniasis (CL). Here, we performed a broad evaluation of natural killer (NK) cell phenotypic and functional features during cutaneous leishmaniasis. We demonstrate for the first time that CL patients present the accumulation of circulating NK cells with multiple features of replicative senescence including low proliferative capacity and shorter telomeres, elevated expression of CD57, KLRG1 but diminished CD27 stimulatory receptor expression. Moreover, they exhibited higher cytotoxic and inflammatory potential than age‐matched controls. The accumulation of circulating senescent NK cells (CD56dim CD57bright) correlated positively with skin lesion size in the same patients, suggesting that they, like circulating senescent CD8+ T cells, may contribute to the immunopathology of CL. However, this senescent population had lower cutaneous lymphocyte antigen expression and so had diminished skin‐homing potential compared with total or senescent CD8+ T cells. This was confirmed in CL skin lesions where we found a predominance of CD8+ T cells (both senescent and non‐senescent) that correlated with the severity of the disease. Although there was also a correlation between the proportions of senescent NK cells (CD56+ CD57+) in the skin and lesion size, this was less evident. Collectively our results demonstrate first‐hand that senescent cytotoxic cells may mediate skin pathology during human cutaneous leishmaniasis. However, as senescent cytotoxic CD8+ T cells predominate in the skin lesions, they may have a greater role than NK cells in mediating the non‐specific skin damage in CL.

Ageing dangerously; homing of senescent CD8 T cells in cutaneous Leishmaniasis

“…In this issue of Immunology we report that the NK cells that expand in CL, like CL‐associated CD8 + T cells, display a senescent and highly cytotoxic phenotype 12 . Unlike the CL CD8 + T cells, however, the NK cells do not express CLA and do not therefore show the same level of skin‐homing potential.…”

“…In this issue of Immunology we report that the NK cells that expand in CL, like CL-associated CD8 + T cells, display a senescent and highly cytotoxic phenotype. 12 Unlike the CL CD8 + T cells, however, the NK cells do not express CLA and do not therefore show the same level of skin-homing potential. Although the NK cells' presence in skin lesions correlates to some extent with the size of CL lesions, and therefore to the severity of the disease, these lesions are dominated by CD8 + T cells.…”

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis

“…Circulating T cells are recruited to the skin during CL ( 33 , 34 ). We next investigated the heterogeneity of ICRs on circulating T cell compartments.…”

“…In our experiments the treatment with PD-1 blockade restored the proliferative capacity of T cells and preferentially augmented IFN-γ relative to TNF-α secretion in both CD4 + T and CD8 + T cell populations. While IFN-γ has been shown to have a protective role in CL, TNF-α secretion may promote pathology in the skin ( 33 , 40 , 41 ). Previous studies have shown that the control of inflammatory potential by blocking TNF-α in vitro or during antimonial therapy for CL in vivo are able to promote faster healing of lesions and higher cure rates than patients with anti- Leishmania treatment alone ( 42 , 43 ).…”

“…Our data also suggests for the first time the co-existence of senescent T cells and ICR-expressing (exhausted) T cells in the patients with CL. While the presence of senescent CD45RA + CD27 - (TEMRA) CD8 + T cells in the circulation express CLA and are closely associated with skin lesion size ( 33 ), PD-1 expressing CD8 + T cells can also home to the skin but are not associated with lesion size. Senescent CD8 + T cells do not express high levels of PD-1 reinforcing the possibility that senescent and exhausted CD8+ T cells are distinct populations, as suggested previously ( 24 ).…”