TGFβ restricts expansion, survival and function of T cells within the tuberculous granuloma


Identification: Gern-Benjamin


Description

TGFβ restricts expansion, survival and function of T cells within the tuberculous granuloma
Authors:
Benjamin Gern MD1, Kristin Adams PhD1, Caleb Stoltzfus PhD2, Courtney Plumlee PhD1, Michael Gerner PhD2,
Kevin Urdahl MD, PhD1,2

Affiliations: 
1Seattle Children’s Research Institute; 2Department of Immunology, University of Washington

Abstract body:
CD4 T cell function at the site of infection is critical for protection against Mtb infection. Although IFNɣ produced by CD4 T cells is highly effective in controlling Mtb systemically, it is much less effective in the lung. Using an ultra-low dose Mtb infection mouse model, we have found that IFNɣ production in Mtb-specific T cells is diminished within the granuloma as compared to distal lung sites and that alleviation of TGFβ signaling on T cells increases IFNɣ production exclusively within the granuloma and reduces bacterial burdens. To further characterize the global effects of TGFβ on T cells during Mtb infection, we generated Mtb-specific T cells that lacked TGFβR (Tg.KO). We then co-transferred naïve Tg.KO cells, and those with intact TGFβR (Tg.WT), into mice infected with Mtb 10 days prior. We found a dramatic decrease in Tg.WT, but not Tg.KO cells in the weeks following transfer. This was associated with increased apoptosis in Tg.WT, and Ki67 positivity in Tg.KO cells. The differentiation profile of these cells was also markedly different, with the majority of parenchymal Tg.KO being KLRG1+, as well as having higher IFNɣ positivity and Tbet MFI. This reveals a role for TGFβ in inhibiting the persistence of terminally-differentiated Mtb-specific T cell subsets, that are capable of producing large amounts of IFNɣ. To isolate the direct suppressive effects of TGFβ signaling on Th1 effectors, we Th1-polarized Tg.KO and Tg.WT cells, and transferred them into Mtb-infected mice with established granulomas. One day following transfer, both cell types trafficked equally into granulomas, and Tg.KO cells were more likely to be IFNɣ+. At five days post transfer, there was already a marked increase in parenchymal Tg.KO cells, which were much more likely to be KLRG1+ and Ki67+. Together, these results indicate that TGFβ plays potent, long-lasting roles in suppressing T cell responses within granulomas at multiple checkpoints. This has important implications for informing host-directed therapy development, especially given that TGFβ inhibitors are already in clinical trials for oncologic indications.

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