Figure 1.

The illustration depicts antigen-driven expansion of effector and regulatory CD4⁺ T cell subpopulations in the spleen along with their migration to and further expansion within the kidney during nephrotoxic serum nephritis in the settings of intact and deficient IL-6 direct signaling within CD4-expressing cells (as demonstrated experimentally by Hegenstein et al.⁸). Left panel: When IL-6 signaling is intact, antigens derived from nephrotoxic sheep IgG drive splenic proliferation of RORγt⁺ T helper (Th)17 and Th1 effectors in addition to FOXP3⁺ conventional regulatory T cells (cTreg) and RORγt⁺/FOXP3⁺ bifunctional Treg (“biTreg”). Migration to and further proliferation of these CD4⁺ T cell subpopulations within the kidneys results in neutrophil-associated Th17-dependent injury (counter-regulated by biTreg) as well as Th17-independent injury (counter-regulated by cTreg and possibly also by biTreg). Right panel: When IL-6 signaling is deficient in CD4⁺ T cells, Th17 expansion in the spleen and kidney is diminished along with associated renal neutrophil infiltration. However, splenic and renal expansion of biTreg is similarly prevented and migration of cTreg to the kidney is reduced. Thus, the loss of IL-6–driven biTreg expansion results in a deficiency of intra-renal regulatory T cell populations and more severe Th17-independent injury. Unchanged intra-renal Th1 cell numbers suggest the presence of additional Th17-independent mediators of glomerular injury.