Fragility of FOXP3+ Treg phenotype

This week I am reviewing two papers dealing with different aspects of FOXP3+ Treg biology. Both papers were published in journal Cell. These are predominantly mouse works so no need to get too excited. 

1st paper was published by Dario Vignali's group (department of Immunology, University of Pittsburgh School of Medicine). They have analyzed role of Neuropilin-1 (Nrp1) in Treg phenotype in tumor context. Neuropilin-1 is a marker of thymic Tregs though this notion is not universally accepted. Interestingly, in mouse tumor model, mouse that expressed Nrp1 on half of its Tregs rejected tumor with the same vigor as mouse expressing Nrp1 on all of its Tregs. 

Furthermore, in the context of tumor challenge, Treg-specific Nrp1 deficiency drastically increased IFN-γ production in both KO and WT Tregs.

It appeared that WT Tregs required sensing of IFN-γ derived from Nrp1KO Tregs to acquire "Nrp1KO-like" phenotype. 

Finally, the authors showed that therapeutic effect of checkpoint inhibitor anti-PD1 antibody against tumor required IFN-γ sensing by Tregs.

In summary, this study showed that Nrp1 deficiency makes Tregs fragile by converting them into IFN-γ producer cells which in turn affect WT Tregs phenotype as well. The reason the authors are using term fragility rather than simply instability has to do, they claim, with the difference in FOXP3 expression between fragile and unstable Tregs. 

In a separate study, the authors showed that Treg depletion inhibits hair regrowth (after depilation). 

However, it is not clear why Tregs should be involved in such physiological process when any other innate cells could do the same.   

David Usharauli

PD-1 signaling assists regulatory T cells when Foxp3 is down

Foxp3⁺ regulatory T cells (Tregs) maintain peripheral tolerance to self. Several molecules expressed by Tregs, such as CTLA-4, play crucial role in maintaining this state of tolerance to self. PD-1 is another such molecule, though its role in Tregs function is less clear.

New paper in PNAS shed some light in PD-1 role in Tregs biology. It found that PD-1 keeps Tregs in shape when Foxp3 level is unstable.

This study arose from unexpected observation in new gene-modified mice where GFP was inserted in Foxp3 locus (mice carrying the IRES-GFPcre reporter KI at the 3′ untranslated region of the FoxP3 gene, FoxP3-GFPcreKI). When these mice were crossed with PD-1KO mice, it was found that male offspring of such cross showed early death, reminiscence of Foxp3KO mice. This was surprising since PD-1KO mice ordinarily do not show such phenotype.

Further experimentation found that GFP insertion affected Foxp3 stability thus resulted in reduced Foxp3 levels in FoxP3-GFPcreKI mice.

Indeed, FoxP3-GFPcreKI/PD-1KO male mice could be rescued with transfer of WT Tregs irrespective of their PD-1 expression indicating that PD-1 function were dispensable Tregs with normal level of Foxp3.

Finally, the authors showed that absence of PD-1 could further destabilize "Foxp3-low" Tregs function (conversion into ex-Foxp3 Tregs) resulting in lethal autoimmunity.

In summary, this study revealed that PD-1 could contribute to Tregs function in situations that affects Foxp3 stability.

David Usharauli