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TGFβ restricts T cell function and bacterial control within the tuberculous granuloma

Benjamin H Gern, Kristin N Adams, Courtney R Plumlee, Caleb R Stoltzfus, Laila Shehata, Kathleen Busman-Sahay, Scott G Hansen, Michael K Axthelm, Louis J Picker, Jacob D Estes, Kevin B Urdahl, Michael Y Gerner

Preprint posted on July 09, 2019 https://www.biorxiv.org/content/10.1101/696534v1

TGF-β: the ugly black duckling that hampers local T cell function in tuberculosis

Selected by Kasturi MAHADIK

Background of the preprint

The term granuloma is synonymous with tuberculosis (TB) for those working with the deadly pathogen, Mycobacterium tuberculosis (Mtb). Upon Mtb infection, granuloma is formed in the lungs by accumulation of bacteria and immune cell infiltrates. Granuloma’s role in the progression of TB however, remains ambiguous. Some report it as a host-protective structure constricting the spread of the pathogen, yet others have shown that it is in fact, a favoured pathogenic niche1. Thus, while we know how a granuloma is structurally formed, we are far from understanding its dynamic environment and their implications on disease evolution2.

Among the many immune cell types occurring in a granuloma are CD4+ T cells; IFNγ produced by these cells is an important determinant of immunity against Mtb3. Several studies indicate that CD4+ T cells may traffic poorly to a granuloma and/or they may be functionally less efficient4,5. Such reports raise a question about the presence of inhibitory mechanisms within the epicenter that restrict T cell-mediated immunity.

Here, Gern and colleagues demonstrate a key role for the cytokine TGF-β in dampening T cell responses in mouse and non-human primate (NHP) lungs upon Mtb infection using a combination of imaging and cytometric analysis. Their findings implicate the immunotherapeutic targeting of TGF-β pathway as an adjunct to existing tuberculosis therapy.

Key findings

Through studies on mycobacteria-infected mice, NHPs and humans, it was clear that lungs of these animals harboured high levels of TGF-β. Authors of this manuscript show that this situation is not, however, synonymous with TGF-β inundation of the lung. Instead, there exists a systematic spatial organization of this cytokine with high levels in the granuloma that recede as we move away from it. They go on to demonstrate that elevated TGF-β is detrimental to the anti-mycobacterial activity of T cells and that this is achieved through the suppression of T cell-derived IFN-γ.

It is well recognized that granulomas formed in mice lack important features of their counterparts in human. At the outset, authors of this manuscript develop a novel model system called the ultra-low dose (ULD) mouse model that faithfully recapitulates the essence of the human granuloma.

Utilizing this model and multiplex confocal imaging coupled to histocytometry, authors uncover that:

  1. CD4+ T cells within the Mtb granuloma produce minimal IFNγ. However, this was not a direct effect of their ability to sense the pathogen, because they recognized Mtb as well as most other CD4+ T cells. Clearly, other/additional repressive mechanisms were waiting to be explored.
  2. There is a robust activation of pathways downstream of TGF-β signaling among CD4+ T cells of the granuloma. This, along with previous literature on the deleterious role of TGFβ in TB, hinted at the potential role of TGFβ signaling in curbing T cell function.
  3. Lack of TGF-β receptors on T cells restores their immune-protective functions
  4. And perhaps the most convincing result for me was when the authors used a chimeric mouse model harboring wild type and TGF-β receptor knockout CD4+ (KO) Mtb-specific T cells. They found nearly 2.5-fold more CD4+ KO T cells travelling to the granuloma than their wildtype counterparts.

 

 

How I believe this pre-print moves the field forward

A picture is worth a thousand graphs and perhaps that is why we are relying on increasing visual representation of our data. However, this must be accompanied by robust quantitation and statistical analysis. This manuscript achieves exactly that. Further, the authors utilize several mouse models (ULD, KO, transgenic, chimeric) in addition to NHPs to validate their hypothesis. Conceptually, this study is important as it reinforces what some among the tuberculosis community believed for a long time, granulomas are fluid structures.

 Open questions

  1. What is the molecular mechanism regulating the TGF-β-IFNγ axis?
  2. Can the findings of elevated TGF-β signaling and diminished IFNγ by CD4+ T cells at the granulomatous region be replicated in the lung sections of infected humans?
  3. While the use of TGF-β receptor KO mice is much appreciated, in reality it is only possible to interfere with TGF-β receptor function using inhibitory therapy. It would be interesting to assess whether any of the existing drugs targeting TGF-β alleviate CD4+ T cell function in the ULD mouse model or even more pertinently, among NHPs.

References

  1. MuseDavis, J and Ramakrishnan, L. The Very Pulse of the Machine: The Tuberculous Granuloma in Motion. Immunity 28,146-8 (2008).
  2. Marakalala, M. J. et al, Inflammatory signaling in human tuberculosis granulomas is spatially organized. Nat Med. 22, 531-8 (2016).
  3. Flynn, J. L. et al, An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp. Med. 178, 2249-2254 (1993).
  4. Moguche, A. O. et al, ICOS and Bcl-6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis. J Exp. Med. 212, 715-728 (2015)
  5. Sakai, S. et al, Cutting Edge: Control of Mycobacterium tuberculosis Infection by a subset of Lung Parenchymal-Homing CD4 T Cells. J Immunol. 192, 2965-2969 (2014).

Tags: mycobacterium, tgf beta

Posted on: 26th July 2019

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