Neuropilin-1 expression is induced on tolerant self-reactive CD8+ T cells but is dispensable for the tolerant phenotype.

Stephanie R. Jackson,Jinyun Yuan,Eddy C. Hsueh,Melissa Berrien-Elliott,Ryan M. Teague,Taishin Akiyama

doi:10.1371/journal.pone.0110707

Abstract

Establishing peripheral CD8+ T cell tolerance is vital to avoid immune mediated destruction of healthy self-tissues. However, it also poses a major impediment to tumor immunity since tumors are derived from self-tissue and often induce T cell tolerance and dysfunction. Thus, understanding the mechanisms that regulate T cell tolerance versus immunity has important implications for human health. Signals received from the tissue environment largely dictate whether responding T cells become activated or tolerant. For example, induced expression and subsequent ligation of negative regulatory receptors on the surface of self-reactive CD8+ T cells are integral in the induction of tolerance. We utilized a murine model of T cell tolerance to more completely define the molecules involved in this process. We discovered that, in addition to other known regulatory receptors, tolerant self-reactive CD8+ T cells distinctly expressed the surface receptor neuropilin-1 (Nrp1). Nrp1 was highly induced in response to self-antigen, but only modestly when the same antigen was encountered under immune conditions, suggesting a possible mechanistic link to T cell tolerance. We also observed a similar Nrp1 expression profile on human tumor infiltrating CD4+ and CD8+ T cells. Despite high expression on tolerant CD8+ T cells, our studies revealed that Nrp1 had no detectable role in the tolerant phenotype. Specifically, Nrp1-deficient T cells displayed the same functional defects as wild-type self-reactive T cells, lacking in vivo cytolytic potential, IFNγ production, and antitumor responses. While reporting mostly negative data, our findings have therapeutic implications, as Nrp1 is now being targeted for human cancer therapy in clinical trials, but the precise molecular pathways and immune cells being engaged during treatment remain incompletely defined.

Highlights

Activated cytotoxic T cells represent a powerful branch of the adaptive immune system, capable of detecting cellular abnormality and protecting the human host from microbial threats and malignancy
We previously reported that recognition of Gag in the immune context leads to CD8+ T cell expansion, acquisition of effector function, and memory formation
In the tolerant context of an Alb:Gag host, these same T cells proliferate briefly but fail to acquire effector function and are largely deleted 8 days after transfer [9,28]. These tolerant T cells were characterized by high expression of multiple inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3) vital for their dysfunctional phenotype [9]

Summary

Introduction

Activated cytotoxic T cells represent a powerful branch of the adaptive immune system, capable of detecting cellular abnormality and protecting the human host from microbial threats and malignancy. These cells are armed with a plethora of effector mechanisms, including cytolytic molecules and proinflammatory cytokines. One mechanism of control is peripheral T cell tolerance, which is critical in preventing immunopathology mediated by excessive CD8+ T cell activity, and is especially important to limit the activation of self-reactive T cells harbored in the periphery of healthy individuals [6]. Tolerance presents a formidable barrier to eliciting anti-tumor immune responses since many cancer antigens are expressed in healthy self-tissue [7]. In an effort to improve treatment options for patients with cancer, extensive work has gone into characterizing the factors that lead to T cell tolerance and the development of strategies that break tolerance toward tumor/self-antigens to augment immunotherapy [8]

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Results

Conclusion