Article
PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis
Registro en:
MOURA, Renan Garcia de et al. PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis. Frontiers in Immunology, v. 12, Article 632667, p. 1 - 12, Mar. 2021.
1664-3224
10.3389/fimmu.2021.632667
Autor
Moura, Renan Garcia de
Covre, Luciana Polaco
Fantecelle, Carlos Henrique
Gajardo, Vitor Alejandro Torres
Cunha, Carla Baroni
Stringari, Lorenzzo Lyrio
Belew, Ashton Trey
Daniel, Camila Batista
Von Zeidler, Sandra Ventorin
Tadokoro, Carlos Eduardo
Guedes, Herbert Leonel de Matos
Zanotti, Raphael Lubiana
Mosser, David
Falqueto, Aloisio
Akbar, Arne N.
Gomes, Daniel Claudio Oliveira
Resumen
Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of
inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not
known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-
1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by
immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in
both CD4+ and CD8+ T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on
skin macrophages compared to healthy controls. The proportions PD1+, but not TIM-3 or
CTLA-4 expressing T cells in the circulation were positively correlated with those in the
lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in
both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative
capacity and IFN-g production, but not TNF-a secretion in response to L. braziliensis recall
antigen challenge in vitro. While we previously showed a significant correlation between the
accumulation of senescent CD8+CD45RA+CD27- T cells in the circulation and skin lesion
size in the patients, there was no such correlation between the extent of PD-1 expression by
circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells
may not contribute to the cutaneous immunopathology. Nevertheless, we identified
exhausted-like T cells in both skin lesions and in the blood. Targeting this population by
PD-1 blockade may improve T cell function and thus accelerate parasite clearance that
would reduce the cutaneous pathology in cutaneous leishmaniasis.