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

Cross-reactivity to fungal antigen drives acquired IFN-γ auto-antibody mediated mycobacteria susceptibility

Inherited genetic deficiency in IFN-γ signaling underlies susceptibility to weakly virulent mycobacteria, such as bacille Calmette-Guérin (BCG) vaccines and nontuberculous mycobacteria. Here, new study in Nature Medicine reported group of patients with acquired susceptibility to mycobacteria due to presence of neutralizing anti-IFN-γ auto-antibodies that could have been results of its cross-reactivity to fungal Aspergillus antigens.

Molecular mimicry hypothesis suggests that if foreign [nonself] antigen shows antigenic similarity to self antigen, then immune response to such nonself antigen could lead to autoimmune diseases due to shared, cross-reactivity. Here, the authors showed that set of patients with mycobacteria infection expressed neutralizing anti-IFN-γ auto-antibodies.

Next, the authors found that conserved KRKR motif of IFN-γ, known to be crucial for the protein’s bioactivity, showed homology to amino acids 105–113 of the ribosome assembly protein Noc2 of Aspergillus terreus.

Indeed, sera from patients with neutralizing anti-IFN-γ auto-antibodies reacted with Noc2 antigen from Aspergillus.

In summary, this study suggested that immune response to Aspergillus in certain individuals carrying specific HLA polymorphism (HLA class II molecules HLA-DRB1*15:02–HLA-DQB1*05:01 and HLA-DRB1*16:02–HLA-DQB1*05:02) could lead to generation of cross-reactive neutralizing anti-IFN-γ auto-antibodies and acquisition of mycobacteria susceptibility.

David Usharauli