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 9 July 2019

Article now published in Cell Host & Microbe at

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.


  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: 26 July 2019


Read preprint (2 votes)

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cell biology category:

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.


List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.


List by Nadja Hümpfer et al.


The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!


List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.


List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020


List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.


List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria


List by Dey Lab, Samantha Seah


Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.


List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20


List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.


List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome


List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)


List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019


List by Dey Lab


Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.


List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.


List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.


List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019


List by Dey Lab


This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.


List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA


List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.


List by Dey Lab, Amanda Haage