On 2015 Dec 16, Lawrence Kane commented:

I took a great interest in this paper, given the ongoing focus of my lab on the mechanisms of Tim-3 signaling and its implications for T cell and mast cell activation. I was encouraged to see that the authors also observed association of Tim-3 with one or more tyrosine kinases in T cells, consistent with our past data Lee J, 2011. However, by contrast with our previous study in Molecular and Cellular Biology Lee J, 2011, they reach a very different set of conclusions regarding the functional effects of ectopic Tim-3 expression. While we consistently observe(d) enhancement of T cell activation after ectopic expression of Tim-3, via either transient transfection or tet induction of a stable cell line, the authors of this study observe inhibition of T cell activation.

What prompted me to write this comment, however, was the fact that the authors were not completely accurate in their representation of our previous data and why it might conflict with theirs. The authors suggest that we used primarily murine Tim-3, expressed in human T cells; however, we have performed many experiments with murine Tim-3 in murine T cells (e.g. Fig. 2D in Lee J, 2011), as well as some experiments with human Tim-3 in human T cells (Fig. 1C in ref. Lee J, 2011). In addition, we had initially generated T cell lines with stable ectopic expression of Tim-3, but these cells invariably lost expression of Tim-3 over time, despite the maintenance of drug selection (unpublished data). This is why we derived the tet-inducible cells used in the latter part of the study (ref. Lee J, 2011).

Thus, in my opinion, it remains to be seen why conflicting conclusions have been reached by different groups regarding the intrinsic effects of Tim-3 on T cell activation and TCR signaling. This is important, given the rapid push to translate findings with immune checkpoint receptors like Tim-3 Mahoney KM, 2015.

On 2015 Dec 16, Lawrence Kane commented:

I took a great interest in this paper, given the ongoing focus of my lab on the mechanisms of Tim-3 signaling and its implications for T cell and mast cell activation. I was encouraged to see that the authors also observed association of Tim-3 with one or more tyrosine kinases in T cells, consistent with our past data Lee J, 2011. However, by contrast with our previous study in Molecular and Cellular Biology Lee J, 2011, they reach a very different set of conclusions regarding the functional effects of ectopic Tim-3 expression. While we consistently observe(d) enhancement of T cell activation after ectopic expression of Tim-3, via either transient transfection or tet induction of a stable cell line, the authors of this study observe inhibition of T cell activation.

What prompted me to write this comment, however, was the fact that the authors were not completely accurate in their representation of our previous data and why it might conflict with theirs. The authors suggest that we used primarily murine Tim-3, expressed in human T cells; however, we have performed many experiments with murine Tim-3 in murine T cells (e.g. Fig. 2D in Lee J, 2011), as well as some experiments with human Tim-3 in human T cells (Fig. 1C in ref. Lee J, 2011). In addition, we had initially generated T cell lines with stable ectopic expression of Tim-3, but these cells invariably lost expression of Tim-3 over time, despite the maintenance of drug selection (unpublished data). This is why we derived the tet-inducible cells used in the latter part of the study (ref. Lee J, 2011).

Thus, in my opinion, it remains to be seen why conflicting conclusions have been reached by different groups regarding the intrinsic effects of Tim-3 on T cell activation and TCR signaling. This is important, given the rapid push to translate findings with immune checkpoint receptors like Tim-3 Mahoney KM, 2015.