Absence of IL-21R or BCL6 in donor T cells reduces expansion of Tph and Trh cells and ameliorates cGVHD. WT or IL-21R^-/- C57BL/6 donor T cells (0.2 × 10⁶) were engrafted with or without WT C57BL/6 TCD-BM cells (2.5 × 10⁶) in lethal total body irradiation–conditioned BALB/c recipients. The BALB/c recipients given TCD-BM alone or with WT-T or IL-21R^-/--T cells were assessed at day 60 after HCT. (A) Curves of percent body weight and percent survival are shown. (B) GVHD pathology scores. (C) Representative staining of IgG deposition in the liver, lung, and skin. Original magnification ×200. (D) Tph cells among CD4⁺ T cells from blood and Trh cells among CD4⁺ T cells from liver and lung were measured and calculated. (E) Percentages of Fas⁺GL7⁺ B cells among total B cells, memory B cells among IgD^- B cells, and plasma cells from the spleen and liver were measured. (F) Serum concentrations of total IgG and anti-dsDNA IgG were measured with ELISA. (G) Tph cells among CD4⁺ T cells from blood and Trh cells among CD4⁺ T cells from the liver and lung of BALB/c recipients after HCT with TCD-BM plus WT-T or BCL6^-/- T cells. (H) Percentages of Fas⁺GL7⁺ B cells among total B cells, memory B cells among IgD^- B cells, and plasma cells from the spleen and liver were measured. (I) Serum concentrations of total IgG and anti-dsDNA IgG were measured with ELISA. (J) Representative confocal images show CD4⁺ and B220⁺ cells in the lung iBALT among WT, IL-21R^-/-, and BCL6^-/- cGVHD mice. Counts of CD4⁺ and B220⁺ cells per iBALT are also shown. Original magnification ×200. Results (mean ± SEM) are combined from 2 replicate experiments. N = 7 to 10. P values were calculated by nonlinear regression with comparison of fits and log-rank test for survival compared with TCD-BM (A), 2-way ANOVA with Holm-Sadik test (B, D, E, G, H), unpaired Student t test (F, I), and 1-way ANOVA with Holm-Sadik test (J). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.