NATURAL KILLERS CELLS: REGULATION MECHANISM EXERCISED BY KLRG1 RECEPTOR AND PROFILE OF DIFFERENTIATION AND FUNCTIONALITY IN CUTANEOUS LEISHMANIOSIS

Name: LUCIANA POLACO COVRE

Publication date: 28/05/2018
Advisor:

Name	Role
DANIEL CLAUDIO DE OLIVEIRA GOMES	Co-advisor *
RODRIGO RIBEIRO RODRIGUES	Advisor *

Examining board:

Name	Role
ALOÍSIO FALQUETO	Internal Examiner *
FAUSTO EDMUNDO LIMA PEREIRA	Internal Examiner *
MARCO CESAR CUNEGUNDES GUIMARÃES	External Examiner *
RODRIGO RIBEIRO RODRIGUES	Advisor *

Summary: Natural killer (NK) cells are a critical component of the innate immune. NK cell
function is tightly regulated by activation or inhibitory receptor signalling. During their
development, NK cells may undergo to an impaired progressive terminal
differentiation, which is associated with defective cell activity. Here, we described
these features during aging and Leishmania infection. We found an increased frequency
of NK cells with high expression of the inhibitory killer cell lectin-like receptor G1
(KLRG1) in older individuals. Terminally differentiated NK cells with high KLRG1
expression spontaneously activate the metabolic sensor AMP-activated protein kinase
(AMPK) and KLRG1 ligation leads to an increase in AMPK activity by preventing
dephosphorylating mediated by PP2C. AMPK activation suppressed NK cell
cytotoxicity, granzyme B and IFN-γ production. Furthermore, NK cells with an active
KLRG1–AMPK axis displayed reduced proliferative potential, decreased telomerase
reverse transcriptase (TERT) expression, reduced telomere length and increased DNA
damage, which are associated with reduced growth and senescence phenotype during
aging. Whether Leishmania infection may affects NK cell maturation in humans has
not been reported yet. Here, we also demonstrated that during localized cutaneous
leishmaniosis (LCL) NK cells with a mature phenotype as shown by increase of
CD56dim subset are augmented. These cells also present decrease of immature markers
as NKG2A, CD161 and CD27 followed by an increase on NKG2C, KIR receptors
(CD158a) and accumulation of terminally differentiated cells characterized as
KLRG1bright and CD57bright. Althought, NK cells during LCL showed high citotoxicity,
granzyme B, inflammatory cytokines production when compared with healthy controls;
they also displayed a low proliferative capacity associated to KLRG1bright and CD57bright
cells. Furthermore, NK cells from LCL patients presented a significative telomere
shortening compared with healthy controls. These findings demonstrate that aging and
Leishmania infection may affect cell phenotype and function, leading to the
accumulation of defective terminally differentiated NK cells. The elucidation of
mechanisms that lead to this cellular commitment, such as the KLRG1 / AMPK
pathway, may be useful to delay or even reverse the deleterious effects of this
phenotype. In addition, the identification of these factors may have important
implications for the development of therapeutic strategies that will aid the functional
maturation process and enhance the NK cell response during infections and cancer.

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