Key Points• Monoclonal antibody blockade of the common g chain attenuates acute and chronic GVHD.• Common g-chain cytokines increase granzyme B levels in CD8 T cells, which are reduced upon CD132 blockade in vivo.The common g chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-g, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3 2/2 T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common g-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. (Blood. 2015;125(3):570-580)

Key Points Cav-1–deficient T cells preferentially differentiate into Tregs, which translates into lower GVHD severity in mice. Reduced TCR:Lck clustering in Cav-1–deficient T cells is responsible for reduced TCR downstream signaling events promoting Treg differentiation.