Saturday, October 22, 2016

FOXP3+ Tregs and allergic TH2 cells recognize mutually exclusive allergic proteins

One reason why it is so difficult to study human FOXP3+ Tregs is that we don't have a good surface marker that selectively identifies human FOXP3+ Tregs from that of conventional T cell memory. As a consequence, we can't easily study antigen-specific human FOXP3+ Tregs.

In this new paper, the authors proposed that expression of CD137 versus CD154 identifies FOXP3+ Tregs versus Tconv in antigen-specific stimulation assay. Using CD137 as a marker, the authors showed that presence of FOXP3+ Tregs specific for variety of nonself antigens, including allergens.

The vast majority of human antigen-specific FOXP3+ Tregs displayed memory CD45RO+ phenotype.

Interestingly, TCR Vbeta analysis revealed mutual exclusivity of FOXP3+ Tregs and Tconv memory.

Next, when analyzing T cells from allergic individuals the authors first confirmed that indeed allergic individuals harbor significantly more allergen-specific TH2 cells.   

However, surprisingly, the authors found that allergic individuals harbor normal numbers of allergen-specific FOXP3+ Tregs.  

To understand this finding, the authors conducted more stringent allergen-specific assay by culturing T cells with individual allergen protein rather than the whole allergen extract as customary (the whole extract contains several related proteins). Indeed, this modified assay showed mutual exclusivity of antigens recognized by human FOXP3+ Tregs and allergic TH2 cells.   

In summary, this paper showed that unlike conventional wisdom, failure of FOXP3+ Tregs to control TH2 cells is antigen-specific. In essence, allergic individuals have specific "holes" in FOXP3+ Tregs repertoire that do not allow them to prevent allergen-specific naive T cells differentiation into allergic TH2 cells. This is first checkpoint. However, simple absence of allergen-specific FOXP3+ Tregs is not sufficient to induce allergy. Second checkpoint for allergy development requires additional factors, not yet fully understood, that promote TH2 response.

David Usharauli 

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