Peripheral Regulatory Cells Immunophenotyping in Kidney Transplant Recipients with Different Clinical Profiles: A Cross-Sectional Study

Figure 5

Hypothetical model by which Bregs, Tregs, and DCregs generate a positive feedback in a three-way loop. IL-10—producing Breg cells favor the differentiation of CD4⁺/CD25⁻ T cells into CD4⁺/CD25⁺ Foxp3-expressing T cells or CD4⁺/CD25⁺/Foxp3⁻ T cells after stimulation through CD40/CD40L or B7.1,B7.2/CTLA-4, respectively, in presence of IL-10. IL-10 induces phosphorylation of STAT3 (pSTAT3) in Foxp3—expressing CD4⁺ and CD8⁺ Tregs, Tr1 and DCs. Tregs with pSTAT3 are capable of suppressing Th17 responses or activation of STAT1 and induce/upregulate IDO activity in DCs through mechanisms requiring CTLA-4 expression, whereas Tr1 suppresses Th1 response and IFN-γ production by cell-cell contact and/or IL-10 production. On the other hand, pSTAT3 in DCs induces downregulation of antigen presenting cell function (CD40, CD80, CD86, MHC I, and HLA-DR expression). Moreover, activated DCs by IFN-α/β/γ express IDO after B7.1/B7.2 ligation to CTLA-4. IDO-expressing DC cells, as Bregs, contribute to regulatory T cell generation (CD4⁺/CD25⁺/Foxp3⁺) from CD4⁺/CD25⁻ T cells through ICOSL-ICOS interaction. Meanwhile, IDO-expressing DC cells contribute to differentiate CD8⁺/CD25⁺/Foxp3⁺ Tregs from CD8⁺/CD25⁻ T cells through PD1-PDL1/2 interaction. CD19⁺/CD24^hi/CD38^hi/CD27⁺ B10 cells suppress TNF-α production by monocytes, via IL-10 expression.