Stat3 Activation in Donor CD4 T-Cells Is Critical for Acute Gvhd

Abstract 1906

Stat3-deficient (Stat3KO) T-cells reportedly are less proliferative due to accelerated apoptosis in the presence of IL-6, and have suppressed IL-2Ra expression. There are conflicting mouse model results concerning Stat3 in graft-versus-host disease (GVHD). Previously, we demonstrated IL-21 signaling is essential for GVHD. As Stat3 is a downstream signaling molecule, clarifying its role in GVHD T-cells is important.

After co-transplantation of bone marrow and wild-type or Stat3KO CD4⁺ T-cells, recipients of the latter developed attenuated GVHD with longer survival than recipients of the former, and their splenic CD4⁺ T-cells exhibited a profound proliferation defect in the mixed lymphocyte reaction (MLR). In contrast to IL-21R-deficient CD4⁺ T-cells, pre-transplantation Stat3KO CD4⁺ T-cells showed similar MLR impairment, suggesting an intrinsic defect. Consistently, proliferation in low-dose anti-CD3 stimulation was defective, but MLR apoptosis was not increased. Neutralizing antibody against IL-2, but not IL-6R, suppressed MLR wild-type CD4 T-cell proliferation, suggesting Stat3KO CD4⁺ T-cells' MLR apoptosis might be attributed to lack of IL-6 contribution.

Pallandre et al. reported Stat3 ablation in CD4 exacerbated GVHD, speculating Stat3 depletion suppressed regulatory T-cell function, leading to accelerated GVHD. Lu et al. analyzed T-cell phosphorylated proteins during allo-activation, demonstrating Stat3 and Erk1/2 are important for this and GVHD. Radojcic et al. showed Stat3KO T-cells cannot induce chronic cutaneous GVHD because of repressed CD4 proliferation and loss of Th17 differentiation. Reasons for differing conclusions are unknown. One possibility is enhanced innate immunity induced by Stat3-siRNA-transduced stem and progenitor cells, consistent with several reports. Our use of Stat3KO T-cells overcame this problem. The latter two reports are consistent with our results. To our knowledge, we report the first direct evidence Stat3 activation in donor CD4⁺ T-cells is critical for acute GVHD. Durant et al. delineated detailed gene regulation in Stat3KO CD4⁺ T-cells, and one of their conclusions—Stat3 is important for CD4⁺ T-cell proliferation—is consistent with our results.