Transiently boosting Vγ9+Vδ2+ γδ T cells early in Mtb coinfection of SIV-infected juvenile macaques does not improve Mtb host resistance

Infect Immun. 2024 Dec 10;92(12):e0031324. doi: 10.1128/iai.00313-24. Epub 2024 Oct 30.

Abstract

Children living with HIV have a higher risk of developing tuberculosis (TB), a disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Gamma delta (γδ) T cells in the context of HIV/Mtb coinfection have been understudied in children despite in vitro evidence suggesting γδ T cells assist with Mtb control. We investigated whether boosting a specific subset of γδ T cells, phosphoantigen-reactive Vγ9+Vδ2+ cells, could improve TB outcome using a nonhuman primate model of pediatric HIV/Mtb coinfection. Juvenile Mauritian cynomolgus macaques (MCM), equivalent to 4- to 8-year-old children, were infected intravenously (i.v.) with SIV. After 6 months, MCM were coinfected with a low dose of Mtb and then randomized to receive zoledronate (ZOL), a drug that increases phosphoantigen levels, (n = 5; i.v.) at 3 and 17 days after Mtb accompanied by recombinant human IL-2 (s.c.) for 5 days following each ZOL injection. A similarly coinfected MCM group (n = 5) was injected with saline as a control. Vγ9+Vδ2+ γδ T cell frequencies spiked in the blood, but not airways, of ZOL+IL-2-treated MCM following the first dose, however, were refractory to the second dose. At necropsy 8 weeks after Mtb, ZOL+IL-2 treatment did not reduce pathology or bacterial burden. γδ T cell subset frequencies in granulomas did not differ between treatment groups. These data show that transiently boosting peripheral γδ T cells with ZOL+IL-2 soon after Mtb coinfection of SIV-infected MCM did not improve Mtb host defense.

Keywords: Gamma delta T cells; Mycobacterium tuberculosis; T cells; human immunodeficiency virus; nonhuman primates; pediatric infectious disease.

MeSH terms

  • Animals
  • Coinfection* / immunology
  • Coinfection* / microbiology
  • Disease Models, Animal
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Macaca fascicularis
  • Mycobacterium tuberculosis* / immunology
  • Receptors, Antigen, T-Cell, gamma-delta* / metabolism
  • Simian Acquired Immunodeficiency Syndrome* / complications
  • Simian Acquired Immunodeficiency Syndrome* / drug therapy
  • Simian Acquired Immunodeficiency Syndrome* / immunology
  • Simian Acquired Immunodeficiency Syndrome* / microbiology
  • Simian Immunodeficiency Virus* / immunology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes / immunology
  • Tuberculosis / drug therapy
  • Tuberculosis / immunology
  • Tuberculosis / microbiology
  • Zoledronic Acid / pharmacology
  • Zoledronic Acid / therapeutic use

Substances

  • Receptors, Antigen, T-Cell, gamma-delta
  • Zoledronic Acid
  • Imidazoles