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

Gern, B.; Adams, K. N.; Plumlee, C. R.; Stoltzfus, C. R.; Shehata, L.; Busman-Sahay, K.; Hansen, S. G.; Axthelm, M. K.; Picker, L. J.; Estes, J. D.; Urdahl, K. B.; Gerner, M. Y.

doi:10.1101/696534

bioRxiv · 10.1101/696534

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

Gern, B.·Adams, K. N.·Plumlee, C. R.·Stoltzfus, C. R.·Shehata, L.·Busman-Sahay, K.·Hansen, S. G.·Axthelm, M. K.·Picker, L. J.·Estes, J. D.·Urdahl, K. B.·Gerner, M. Y.

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Abstract

Interferon gamma (IFN{gamma}) produced by CD4 T cells is required for immune containment of Mycobacterium tuberculosis (Mtb) infection. Despite this, IFN{gamma} plays a minor role in CD4 T cell-mediated immunity within the lung. In this study, we use a recently-developed murine model of physiologic Mtb infection coupled with advanced quantitative imaging to demonstrate that IFN{gamma} production by Mtb-specific T cells is rapidly extinguished within the granuloma, but not in unaffected areas of the lung. This is mediated via localized immunosuppression through cell-intrinsic TGF{beta} signaling in effector T helper 1 cells within the granuloma, and blockade of TGF{beta} signaling in T cells results in improved immune cell function and decreased pulmonary bacterial burden. These findings uncover a potent immunosuppressive mechanism associated with Mtb infection and provide potential targets for host-directed therapy.

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Gern, B., Adams, K. N., Plumlee, C. R., Stoltzfus, C. R., Shehata, L., Busman-Sahay, K., Hansen, S. G., Axthelm, M. K., Picker, L. J., Estes, J. D., Urdahl, K. B., Gerner, M. Y.. 2019-07-09. TGFβ restricts T cell function and bacterial control within the tuberculous granuloma. https://doi.org/10.1101/696534

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