T cell-specific Smad4 controls the lethal autoimmunity

I was very excited when I saw this title in journal Immunity and then utterly disappointed after reading the actual paper.

The only noteworthy result from this paper is depicted in Figure 1A. The authors showed that compared to mice single deficient for T cell-specific TGF-beta RII signaling (RII-KO), mice double deficient for T cell-specific TGF-beta RII and Smad4 signaling (RII-S4 DKO) were protected from lethal autoimmunity.

Bone marrow (BM) chimera experiments revealed that unlike RII-KO BM cells, RII-S4 DKO BM cells could generate Foxp3+ Tregs in vivo (though 2-fold less compared to WT BM cells).  

Strangely, however, in vitro experiments showed that RII-S4 DKO T cells were dramatically deficient in generating Foxp3+ Tregs (though they efficiently differentiated into TH1 or TH2 phenotypes).

Finally, the authors showed that mice single deficient for Smad4 (S4-KO) were not able to efficiently reject OVA-expressing tumor (no similar data for RII-S4 DKO mice were produced).

In summary, in my opinion, these results were not ready for publication in Immunity. The authors failed to follow their best Figure 1A result and provide any convincing argument that could explain their observation. It is clear that T cells deficient in Smad4 failed to accumulate in normal numbers in vivo upon antigen encounter (memory failure?), but the fact that Smad4-KO T cells could efficiently differentiate into effector T cells makes all these results confusing. Also, it is not clear whether absence of lethal autoimmunity in RII-S4 DKO mice has to do with the presence of normal number of fully functioning Foxp3 T cells.

David Usharauli