Inducible T-Cell Co-Stimulator Impacts Chronic Graft-Versus-Host Disease by Regulating Both Pathogenic and Regulatory T Cells

The incidence of chronic graft-versus-host disease (cGVHD) is on the rise and still the major cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation (HCT). Both donor T and B cells contribute to the pathogenesis of cGVHD. Inducible T-cell co-stimulator (ICOS), a potent co-stimulatory receptor, plays a key role in T-cell activation and differentiation. Yet, how ICOS regulates the development of cGVHD is not well understood. Here, we investigated the role of ICOS in cGVHD pathogenesis using mice with germline or regulatory T cell (Treg)-specific ICOS deficiency. The recipients of ICOS−/− donor grafts had reduced cGVHD compared with wild-type controls. In recipients of ICOS−/− donor grafts, we observed significant reductions in donor T follicular helper (Tfh), Th17, germinal center B-cell, and plasma cell differentiation, coupled with lower antibody production. Interestingly, Tregs, including follicular regulatory T (Tfr) cells, were also impaired in the absence of ICOS. Using ICOS conditional knockout specific for Foxp3+ cells, we found that ICOS was indispensable for optimal survival and homeostasis of induced Tregs during cGVHD. Furthermore, administration of anti-ICOS alleviated cGVHD severity via suppressing T effector cells without affecting Treg generation. Taken together, ICOS promotes T- and B-cell activation and differentiation, which can promote cGVHD development; however, ICOS is critical for the survival and homeostasis of iTregs, which can suppress cGVHD. Hence, ICOS balances the development of cGVHD and could offer a potential target after allo-HCT in the clinic

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity

PIM kinase family members play a crucial role in promoting cell survival and proliferation via phosphorylation of their target substrates. In this study, we investigated the role of the PIM kinases with respect to T cell responses in transplantation and tumor immunity. We found that the PIM-2 isoform negatively regulated T cell responses to alloantigen, in contrast to the PIM-1 and PIM-3 isoforms, which acted as positive regulators. T cells deficient in PIM-2 demonstrated increased T cell differentiation toward Th1 subset, proliferation, and migration to target organs after allogeneic bone marrow transplantation, resulting in dramatically accelerated graft-versus-host disease (GVHD) severity. Restoration of PIM-2 expression markedly attenuated the pathogenicity of PIM-2-deficient T cells to induce GVHD. On the other hand, mice deficient in PIM-2 readily rejected syngeneic tumor, which was primarily dependent on CD8(+) T cells. Furthermore, silencing PIM-2 in polyclonal or antigen-specific CD8(+) T cells substantially enhanced their antitumor response in adoptive T cell immunotherapy. We conclude that PIM-2 kinase plays a prominent role in suppressing T cell responses, and provide a strong rationale to target PIM-2 for cancer immunotherapy.Biostatistics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; University of Arizona Cancer Center [P30 CA023074]; NIH [R01CA173200, R01 CA169116, R01 AI118305, R01 HL137373, R21 CA192202]; DOD [W81XWH-12-1-0560]; SmartState Endowment in Cancer Stem Cell Biology & Therapy ProgramThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). DCs play critical roles in GVHD induction. Modulating autophagy represents a promising therapeutic strategy for the treatment of immunological diseases. Complement receptors C3aR/C5aR expressed on DCs regulate immune responses by translating extracellular signals into intracellular activity. In the current study, we found that C3aR/C5aR deficiency enhanced ceramide-dependent lethal mitophagy (CDLM) in DCs. Cotransfer of host-type C3aR-/-/C5aR-/- DCs in the recipients significantly improved GVHD outcome after allogeneic HCT, primarily through enhancing CDLM in DCs. C3aR/C5aR deficiency in the host hematopoietic compartment significantly reduced GVHD severity via impairing Th1 differentiation and donor T cell glycolytic activity while enhancing Treg generation. Prophylactic treatment with C3aR/C5aR antagonists effectively alleviated GVHD while maintaining the graft-versus-leukemia (GVL) effect. Altogether, we demonstrate that inhibiting C3aR/C5aR induces lethal mitophagy in DCs, which represents a potential therapeutic approach to control GVHD while preserving the GVL effect