Foxp3+ Tregs control CD8 T cells, but not CD4 T cells, by IL-2 deprivation

This week Nature Immunology published another interesting study from Rudensky's lab done in collaboration with Jason Fontenot (who apparently moved from Biogen to Juno Therapeutics). So, if you are a fan of Tregs, below is my short scientific overview of that paper.

This study tries to answer what role IL-2 signaling plays in already established Foxp3+ Tregs. For such study mice with germline deficiency in IL-2 signaling cascade would have been impractical since IL-2's effect on thymocytes and etc. Instead, the authors went to already well established path of using mice lacking "molecule of interest" specifically in Tregs. In this case several Foxp3-cre mice were used, such as: l2rb^fl/flFoxp3^Cre, Il2ra^fl/flFoxp3^Cre, Stat5a^fl/flStat5b^fl/flFoxp3^Cre, Rosa26^Stat5bCAIl2rb^fl/flFoxp3^Cre and Rosa26^Stat5bCAIl2ra^fl/flFoxp3^Cre, Rosa26^Stat5bCAFoxp3^Cre–ERT2. All these gene-modified mice allows specific targeting of Foxp3+ Tregs.

Unsurprisingly, mice lacking IL-2Rβ or IL-2Rα or STAT5 signaling specifically in Tregs developed autoimmunity.

Surprisingly, however, while constitutive expression of STAT5 in Tregs lacking IL-2 signaling receptors (IL-2Rβ or IL-2Rα) could rescue mice from "CD4 effector phenotype" and early death, these mice still developed immunopathology later due to massive expansion of CD8 effector/memory cells, suggesting that sensing of IL-2 by Tregs, so called "IL-2 sink", was necessary to specifically control CD8 T cells, but not CD4 T cells.

In summary, this study suggests that Tregs are using distinct mechanisms to control CD4 and CD8 T cells. It kind of makes sense because MHC class-II restricted CD4+ Tregs cannot interact the same way with MHC class-I restricted CD8+ T cells as they could with conventional MHC class-II restricted conventional CD4+ T cells.

David Usharauli

TCR derived from gut Foxp3+ Tregs can generate two distinct T cell phenotypes

This is my first review of a paper published in new journal from Science family called Science Immunology.

This paper deals with the relationship between TCR and origin of peripheral [gut-residing] Foxp3+ regulatory T cells. Specifically, the authors have used method called somatic cell nuclear transfer (SCNT) that allowed generation a transnuclear (TN) mouse that carries a TCR cloned from gut tissue Foxp3+ Tregs. 

First surprising observation was that these Foxp3+ TCR transnuclear but otherwise unmanipulated mice (called pTreg TN/RKO mice, on RAG KO base) had no Foxp3+ Tregs neither in the thymus or the peripheral lymph nodes (mLNs).

Second, the authors found that transnuclear mice instead harbored specialized IFN-γ⁺CD8αα⁺ intraepithelial lymphocyte (IEL) subset.

Indeed, adoptive transfer Foxp3+ TCR transnuclear T cells into WT host revealed that donor T cells could differentiate either into CD8αα⁺ intraepithelial lymphocyte (IEL) subset or acquire Foxp3 marker as representative of peripheral Treg subset. Of note, development of both of these subsets dependent of gut microbiota.

Finally, the authors showed that donor Foxp3 transnuclear T cells transferred into T cell-deficient hosts did not induce gut inflammation even if they were derived from scurfy background (lacking ability to express functional Foxp3 protein), implying that functionality of CD8αα⁺ intraepithelial lymphocyte (IEL) derived from Foxp3+ TCR T cells did not cause any tissue pathology.

In summary, this study showed that depending on circumstances TCR derived from intestine Foxp3+ Tregs can drive development of two distinct subsets with immunoregulatory role: CD8αα⁺ intraepithelial lymphocyte (IEL) subset or peripheral Foxp3+ Treg subset.  

David Usharauli

Selective Tregs elimination within tumor using CD25 antibody coupled to near-infrared photoimmunotherapy

Regulatory T cells (Tregs) inhibit immune responses. When considering autoimmune diseases or allergies, this function of Tregs has beneficial effect on host. The same function, however, could be "hijacked" by tumors to evade immune destruction. So far, selective depletion of tumor-associated Tregs has not been achieved in clinical settings.

New paper in Science Translational Medicine suggested novel approach to eliminate tumor-associated Tregs: application of anti-CD25 F(ab)2 fragments coupled to photo-active silica-phthalocyanine dye (IR700)  and exposed to near-infrared photo-immunotherapy (NIR-PIT). 

First, in vitro experiments showed that when CD25+ cells are exposed to anti-CD25 F(ab)2-IR700 and subjected to NIR-PIT, they undergo cell death.

Since tumors accumulate high frequency of Tregs, the authors conducted NIR-PIT experiments in vivo. When tumor-challenged mice were exposed to anti-CD25 F(ab)2-IR700 and subjected to NIR-PIT, the authors observed temporal delay in tumor growth and improved survival. 

Of note, tumors located at the distant sites away from direct exposure of NIR-PIT also display growth delay after anti-CD25 F(ab)2-IR700/NIR-PIT application, indicating system-wide after-effect of local elimination of Tregs by NIR-PIT.

Finally, the authors found that anti-tumor effect of anti-CD25 F(ab)2-IR700/NIR-PIT application was mediated by IFN-gamma derived from CD8 T and NK cells.

In summary, the authors claim that this less invasive procedure could selectively eliminate CD25+ Tregs (but not effector T cells) in tumors  and improve survival of tumor-challenged host.

David Usharauli