Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease

Abstract

The myeloid differentiation factor 88 signaling has a crucial role in activation of both innate and adoptive immunity. Myeloid differentiation factor 88 transduces signal via Toll-like receptor and interleukin-1 receptor superfamily to NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. Myeloid differentiation factor 88/interleukin-1 receptor-associated kinase 4 pathway plays an important role not only in innate immunity but also T-cell immunity; however, its role in donor T cells on graft-versus-host disease pathophysiology remains to be elucidated. We addressed this issue by using myeloid differentiation factor 88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation.While myeloid differentiation factor 88-deficient and wild-type T cells proliferated equivalently after transplantation, myeloid differentiation factor 88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe graft-versus-host disease compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. These results thus demonstrate that donor T-cell myeloid differentiation factor 88/ interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against graftversus-host disease after allogeneic hematopoietic stem cell transplantation.

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease

“…Administration of the inhibitor ameliorated the inflammatory environment, increased tissue repair in GvHD target organs and suppressed lethal GvHD. Administration of an IRAK-4 inhibitor also ameliorated GvHD in a mouse model of allo-SCT ( 19 ). In this model, MyD88 in donor T cells was not essential for graft-versus-leukemia (GvL) effects.…”

When rubber meets the road: how innate features of adaptive immune cells play critical roles in transplant alloimmunity

“…This is the first study to show TLR7 tolerization results in reduced GvHD. Similarly, another study has shown the impact of TLR-signaling in T cells in GvHD by providing evidence that MyD88 contributes to both T-cell survival and differentiation in GvHD [16]. These studies suggest that TLR and MyD88 signaling are important in the GvHD T-cell response, and that tolerization through this pathway represents a potential effective T-cell therapeutic in GvHD.…”

The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota

“…In contrast to anti-CD40, we found a critical role for MyD88 signaling in anti-CD137-induced CD8 + T cell liver infiltration and liver damage, as well as systemic IFNγ secretion. MyD88-mediated sensing of the microbiota has been shown to influence T cell responses in other pathologies, such as type 1 diabetes and GVHD, directly 60 or indirectly by influencing innate immune cell populations that subsequently influence T cell responses. 61 Finally, we found that antibiotic treatment significantly reduced the liver damage induced by anti-CD137 + anti-PD1 combination therapy without impairing anti-tumor efficacy, which is of particular importance given this combination therapy is being actively investigated in clinical trials.…”