Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE

Abstract

Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

“…Indeed, astrocytes, the type of glial cells which encircle intracranial gliomas, can produce significant amounts of VEGF as well as matrix metalloproteinases and may thus promote tumor growth and invasion [49]. Moreover, neurons can promote Treg induction via TGF-b secretion, and thus may be at least in part responsible for the relative increase of Tregs observed in intracranial gliomas [50]. We show here that a glioma residing in the CNS is not simply ignored by the immune system, and that the immuno-modulatory capacity of the GL261 glioma is not purely an inherent property of this tumor.…”

Protein/DNA vaccine‐induced antigen‐specific Treg confer protection against asthma

“…However in this study, we identify the T cell with a phenotypic resemblance to Tr1 of CD4 À /CD25 À /Foxp3 1 /IL-10 1 /IFN-g/TGFb 1 after the induction of co-immunization with DNA and protein protocol, this Tr1 like cells can successfully suppress the development of asthma-like inflammations in an antigen-specific manner in mice. Although many aspects of the mechanisms by which the regulatory cells function remain to be elucidated, it has been well established that Treg use both cell-to-cell interactions and/or the production of 34,38,39]. Treg, particularly for the thymic-derived CD4 1 CD25 1 Treg, express the Foxp3 gene and mediate the suppressive function in an antigen-non-specific manner [40,41].…”

“…Besides IL-10, TGF-b has been also demonstrated to be an important cytokine related to Tr's function [17,33,34]. We tested TGF-b expression using RT-PCR in the CD4 1 CD25 À T cells from the co-immunized mice (Fig.…”

“…Since the transcriptional factor Foxp3 has been demonstrated to be a hallmark of the Treg [31,32], the co-immunization-induced CD4 1 CD25 À Treg can be thus categorized into the regulatory class of T cells with a unique phenotype. Besides IL-10, TGF-b has been also demonstrated to be an important cytokine related to Tr's function [17,33,34]. We tested TGF-b expression using RT-PCR in the CD4 1 CD25 À T cells from the co-immunized mice (Fig.…”

Regulatory T cells and immune computation

“…Physiological levels of hormones such as estrogens can induce T reg [31]. The state of neurons in the central nervous system can induce the conversion into T reg of encephalitogenic effector T cells, and thereby suppress autoimmune encephalomyelitis [32]. Tumor cells are notorious for generating signals that upregulate T reg , leading to evasion by the tumor of immune surveillance [33].…”