Tuesday, May 30, 2017

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

Saturday, May 6, 2017

antigen-specific Foxp3+ Tregs maintain tolerance in HLA-linked autoimmunity

This week Nature published new paper that has features of textbook studies. In it the authors showed that in human HLA transgenic mice model of Goodpasture disease [HLA+antigen]-specific Foxp3+ Tregs protected against autoimmune disease development.

Goodpasture disease is an "HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cells [reactive to] self-epitope derived from the α3 chain of type IV collagen (α3135–145)". In humans presence of HLA-DR15 allele increases disease risk, while presence of HLA-DR1 allele is shown to be dominantly protective in trans with HLA-DR15.

Interestingly enough the authors reported similar pattern of HLA dependency in mouse model of human Goodpasture disease. Here, DR15+ mice were susceptible to disease development. DR1+ mice were resistant to disease development and DR15+DR1+ double-positive mice were healthy except when Tregs were depleted (all mice were on Fcgr2b−/− background, +/- Treg depletion, + immunization with peptide α 3135–145). 

It is not clear how Treg specific for DR1+peptide protects against autoreactive T cells specific for DR15+peptide. It is possible that there is some similarities between these HLA+peptides (cross-reactivity).

David Usharauli