MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Abstract

Understanding mechanisms of immune regulation is key to developing effective immunotherapies for autoimmunity and cancer; however, many regulatory mechanisms have not been elucidated. By analyzing T cell motility and activation at the disease site as well as disease progression, we examined the role of mononuclear phagocytes in driving regulation of effector T cells in type 1 diabetes and melanoma. We report that mononuclear phagocytes in the islets impair T cell responsiveness to antigen by preventing antigen-mediated T cell arrest.Mononuclear phagocytes in the autoimmune lesion express the TAM family receptor tyrosine kinase Mertk which functions in efferocytosis. Inhibition or deficiency of Mertk led to a release from T cell regulation characterized by enhanced T cell arrest in pre-diabetic islets and at the tumor site. This T cell arrest was accompanied by increased T cell-antigen presenting cell interactions as well as increased antigen experience and effector function by T cells in the islets.Notably, the effect of Mertk inhibition on T cell regulation was only seen at the disease site in the islets, not in draining lymph nodes. Inhibition of Mertk-dependent T cell regulation culminated in the rapid acceleration of autoimmune pathology and disease. In human islets, the number of Mertk-expressing cells were increased in remaining insulin-containing islets from type 1 diabetic patients, suggesting that they might have a protective role in human disease. These data indicate that Mertk signaling in mononuclear phagocytes drives T cell regulation that functions specifically at the disease site in peripheral tissues through a mechanism that prevents T cell arrest and response to antigen.

Autoimmunity in motion: Mechanisms of immune regulation and destruction revealed by in vivo imaging*

“…To elucidate mechanisms by which T cell responsiveness to antigen was suppressed in islets with advanced infiltration, Lindsay et al, 89 analyzed the role of the mononuclear phagocyte populations in the islets. Depletion of islet macrophages and DCs resulted in increased arrest of T cells in the islets.…”

“…These data suggest that, Mertk signaling in mononuclear phagocytes protected the islets from rapid islet destruction by suppressing the responsiveness of islet antigenspecific T cells to their antigen. 89 Notably, increased numbers of Mertk-expressing cells were found in the insulin-containing islets of human T1D patients, 89 suggesting that Mertk may function to protect human islets from destruction.…”

“…Autoimmunity and tumor immunity represent flip sides of the same coin, utilizing many of the same mechanisms to control the immune response. For example, Lindsay et al 89 demonstrated that the same Mertk‐dependent mechanism that regulates T cells in the islets during T1D also regulates T cells at a tumor site. This is further highlighted by the fact that checkpoint blockade for tumor treatment can have the immune mediated side effect of inducing autoimmunity such as fulminant T1D.…”

Abnormal Changes of Monocyte Subsets in Patients With Sjögren’s Syndrome

“…Mononuclear phagocytes (MNPs) are the most common innate immune cells with key roles in both immunity and autoimmunity (8)(9)(10)(11). MNPs in blood are mainly composed of monocytes and dendritic cells (DCs), both of which have heterogenerous subsets with distinct phenotypes (12,13).…”