IFN-γ-independent control of M. tuberculosis requires CD4 T cell-derived GM-CSF and activation of HIF-1α

Van Dis et al. (BioRxiv) doi: 10.1101/2021.12.16.473015

Keywords

  • CD4 T cells

  • Macrophages

  • Mycobacterium tuberculosis

 

Main Findings

This paper aims at understanding the role of CD4 T cells in the control of M. tuberculosis by Macrophages. The authors showed that CD4 T cells exhibit IFN-γ-independent control in infected macrophages via secreted and proteinaceous effector which they proved is GM-CSF. This control requires the expression of HIF-1α by the Macrophages which also leads to a metabolic switch to aerobic glycolysis and formation of lipid droplets. Nonetheless, this mechanism is independent of NO production. 

Limitations

  • There is no further exploration on how the HIF-1α is stable if NO is no longer produced

  • They only managed to replicate the results with recombinant GM-CSF in peritoneal MΦ.

  • They only explored the possibility of increased phagocytosis, while there are multiple mechanisms for control intracellular bacteria. This is not discussed in the paper. 

  • Most of the paper results are obtained from in-vitro model of M. tuberculosis infection in Macrophages. However, it is not discussed the possible differences between this system and the granuloma environment which is found in vivo.

Significance/Novelty

The paper has a very clear aim at expanding our current knowledge on how CD4 T cells affect the control of M. tuberculosis by stimulating Macrophages. The results from this study highlight GM-CSF as a bactericidal and emphasize the importance of HIF-1α in intracellular immunity. Understanding the alternative mechanisms that lead to the elimination of M. tuberculosis is of importance for the current efforts on Vaccine development. 

Credit

Reviewed by Laura M. Palma Medina as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology  (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM).