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

Front Immunol. 2024 Oct 21:15:1475146. doi: 10.3389/fimmu.2024.1475146. eCollection 2024.

Abstract

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.

Keywords: CD4-CTL; Leishmania braziliensis; bystander cytotoxicity; cutaneous leishmaniasis; senescent cells.

MeSH terms

  • Adult
  • Bystander Effect / immunology
  • CD4-Positive T-Lymphocytes* / immunology
  • Cellular Senescence* / immunology
  • Cytotoxicity, Immunologic
  • Female
  • Granzymes / metabolism
  • Humans
  • Leishmaniasis, Cutaneous* / immunology
  • Leishmaniasis, Cutaneous* / parasitology
  • Leishmaniasis, Cutaneous* / pathology
  • Male
  • Middle Aged
  • Skin* / immunology
  • Skin* / parasitology
  • Skin* / pathology
  • T-Lymphocytes, Cytotoxic / immunology
  • Young Adult

Substances

  • Granzymes
  • GZMB protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Fundação de Amparo a Pesquisa do Espírito Santo (Grants 2022-1TCGX and 2022-H5GWQ); National Council for Scientific and Technological Development -CNPq (Grant 402280/2022-9); Coordination for the Improvement of Higher Education Personnel -CAPES -Brazil (Scholarship 88887.518716/2020-00); Medical Research Council (UK) (Grant MR/T015853/1); National Institutes of Health (R01-AI-149456) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brasil (CAPES) -Finance Code 001.