Frontiers in Immunology (Oct 2024)

Lesional senescent CD4+ T cells mediate bystander cytolysis and contribute to the skin pathology of human cutaneous leishmaniasis

  • Luciana Polaco Covre,
  • Luciana Polaco Covre,
  • Luciana Polaco Covre,
  • Carlos Henrique Fantecelle,
  • Renan Garcia de Moura,
  • Paola Oliveira Lopes,
  • Isabela Valim Sarmento,
  • Celio Geraldo Freire-de-Lima,
  • Debora Decote-Ricardo,
  • Herbert Leonel de Matos Guedes,
  • Herbert Leonel de Matos Guedes,
  • Alessandra Marcia da Fonsceca-Martins,
  • Lucas Pedreira de Carvalho,
  • Edgar Marcelino de Carvalho,
  • David M. Mosser,
  • Aloisio Falqueto,
  • Arne N. Akbar,
  • Daniel Claudio Oliveira Gomes,
  • Daniel Claudio Oliveira Gomes

DOI
https://doi.org/10.3389/fimmu.2024.1475146
Journal volume & issue
Vol. 15

Abstract

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Cytotoxic activity is a hallmark of the immunopathogenesis in human cutaneous leishmaniasis (CL). In this study, we identified accumulation of CD4+ granzyme B producing T cells with increased cytotoxic capacity in CL lesions. These cells showed enhanced expression of activating NK receptors (NKG2D and NKG2C), diminished expression of inhibitory NKG2A, along with the upregulation of the senescence marker CD57. Notably, CD4+ T cells freshly isolated from CL lesions demonstrated remarkable capacity to mediate NL-like bystander cytolysis. Phenotypic analyses revealed that lesional CD4+ T cells are mainly composed of late-differentiated effector (CD27-CD45RA-) and terminally differentiated (senescent) TEMRA (CD27-CD45RA+) subsets. Interestingly, the TEMRA CD4+ T cells exhibited higher expression of granzyme B and CD107a. Collectively, our results provide the first evidence that senescent cytotoxic CD4+ T cells may support the skin pathology of human cutaneous leishmaniasis and, together with our previous findings, support the notion that multiple subsets of cytotoxic senescent cells may be involved in inducing the skin lesions in these patients.

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