Journal Club: Tox & T cell exhaustion

Courtney Matson : August, 15, 2019

TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection – Alfie, F. et al. ; Nature. 2019 Jul;571(7764):265-269

In addition to the above paper, also see the related papers :

Courtney’s comments: I really liked that the authors had multiple viral infections to drive home the point that the induction of TOX and the dysfunctional phenotype is dependent on chronic antigen stimulus. The lower affinity and titrating in gp33KO virus was a really great way to show this. Also, I thought the correlation with the human data in HCV patients was really interesting. It is not always as striking of a phenotype when translating mouse observations into humans and considering that this is also seen in the additional papers with cancer patients suggests that TOX plays a conserved role in mediating the effects. This paper was heavier on the sequencing analysis which lends support for the other papers cellular experiments describing the role of TOX in regulating a progenitor pool of dysfunctional T cells

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  1. In this paper, we first started discussing the two different LCMV models that are commonly used to track both acute and chronic T cell responses (armstrong and Clone 13). These authors used chronic vs acute LCMV and P14 transgenic T cells to to test differential gene expression between exhausted and functional T cells. The increase in TOX, is the focus of the paper discussing. Increased Tox expression seemed to correlate with higher levels of PD-1 and more “dysfunctional” phenotypes of T cells, but they found that in TOXdelta models that these cells had a decreased survival, so there appears to be some sort of trade-off in which the TOX increases in times of chronic antigen stimulation but then also promotes pro-survival signals so these cells stick around longer. This prompted us to talk about the utility of having a population of “dysfunctional” cells hanging around, and I was curious how this was unique from the paradigm we are taught about memory T cell subsets that are long lasting.

  2. Tox seems to nicely fit as a regulator of T cell hypofunction that balances pathogen clearance with immunopathology, as Fig 2F shows that TOXdelta animals have lower systemic viral load at 8 dpi while ED Fig 4h-k shows that TOXdelta animals also had significant lung and liver pathology compared to WT animals, despite similar viral load in those tissues (ED Fig 4g). It’s also interesting that, as ED fig 2e-o show, deletion at 20 dpi yielded no difference in PD-1 expression or KLRG1+ cell frequency, suggesting that Tox is necessary for establishing a hyporesonsive pool of cells early. These data also suggest that deletion of Tox from adoptive cell therapies like CARs might yield prolonged effector responses. Finally, Gideon’s question as to why “dysfunctional” cells are maintained is a good one, and his comment that the TCF-1+ progenitor model for these cells resembles conventional Tcm is even better. Fig 4e showed that TCF1+ cells are enriched for CD62L and CCR7 expression but have low CD25 levels (by transcriptomics), showing that they even follow conventional phenotypic paradigms. Considering our discussion of the hypothesis that it is likely advantageous for the immune response to slowly clear a persistent, but not immediately life-threatening pathogen rather than sustaining a maximal response for extended time and causing immunopathology, it seems as though these cells are maintained just like any other memory cell but that they are only “hyporesponsive” when compared to the maximum response to an acute antigen. So, I would suggest that they are appropriately responsive to their “chronic” antigen. Although this paper doesn’t directly address this, my impression is that there is room to rethink the T cell “exhaustion” “nonresponsiveness” etc paradigm and reframe it from dysfunction to function that is appropriately for the context of antigen. (Hope that was clear, it was kind of stream-of-consciousness).

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