Type II Collagen Induces Peripheral Tolerance in BALB/c Mice via the Generation of CD8+ T Regulatory Cells

Shukkur M Farooq,Hossam M Ashour,Mohammed Alsharifi

doi:10.1371/journal.pone.0048635

Abstract

Antigens introduced into the anterior chamber (AC) of the eye induce a potent form of antigen-specific peripheral immune tolerance termed AC-associated immune deviation (ACAID), which prevents inflammatory immune responses and is characterized by impaired delayed-type hypersensitivity (DTH) responses. Type-II collagen (CII) is a fibrillar protein expressed exclusively in cartilage tissues. Although of its clinical relevance to Rheumatoid arthritis, aging, and osteoarthritis, there have been no studies to date to test if CII has the ability to induce ACAID. We hypothesized that ACAID could be generated via AC injection of CII in BALB/c mice. Using a DTH assay, the hypothesis was supported and led to another hypothesis that CII is capable of inducing specific immune tolerance via CD8+ T regulatory cells (Tregs). Thus, we performed functional local adoptive transfer (LAT) assays to examine the regulatory roles of spleen cells, T cells, and CD8+ T cells in the specific immune regulation induced by CII injection into the AC. Results indicated that CII induced ACAID when injected into the AC. Spleen cells of mice injected with CII in the AC significantly suppressed DTH responses. The T cell compartment of the spleen was capable of expressing this suppression. CD8+ Tregs could solely express this CII-driven suppression and even exerted more noticeable suppression than spleen cells or splenic T cells. This study suggests a crucial role for CD8+ Tregs in mediating CII-driven ACAID-mediated immune tolerance. This could have therapeutic implications in Rheumatoid arthritis, aging, osteoarthritis, and other diseases in which CII is involved.

Highlights

Antigens introduced into the anterior chamber (AC) of the eye induce a potent form of antigen-specific peripheral immune tolerance termed AC-associated immune deviation (ACAID), which prevents inflammation and related deleterious peripheral immune responses [1,2,3]
Following antigenic entry into the eye, bone marrowderived F4/80+ antigen presenting cells (APCs) of the iris and ciliary body pick the antigen before migrating into the systemic circulation and homing to the spleen where they develop antigen-specific tolerance through the generation of T regulatory cells (Tregs) [10,11]
The F4/80+ molecule has a key role in the differentiation of antigen-specific CD8+ Tregs via direct interaction of CD1d+ APC with NK T cells [22]

Summary

Introduction

Antigens introduced into the anterior chamber (AC) of the eye induce a potent form of antigen-specific peripheral immune tolerance termed AC-associated immune deviation (ACAID), which prevents inflammation and related deleterious peripheral immune responses [1,2,3]. ACAID was shown to induce antigen-specific inhibition of Th2 mediated pulmonary pathology [8]. In ACAID, resident ocular tissue F4/80+ antigen presenting cells (APCs) process antigens entering into the AC, internalize the antigen before gaining access into the bloodstream and eventually into the spleen [10,11]. These ocular APCs interact with marginal zone B cells, cd T cells, and NK T-cells in the spleen in order to induce the differentiation of CD4+ afferent Tregs and CD8+ efferent Tregs [7,10,12,13]. CD8+ Tregs have been shown to have major suppressive roles in autoimmune disease [14]

Methods

Results

Conclusion