Ocular Immune Privilege Promoted by the Presentation of Peptide on Tolerogenic B Cells in the Spleen. II. Evidence for Presentation by Qa-1

Abstract

Ocular immune privilege is the result of several unique features of the eye, including the systemic down-regulation of Th1 immune responses to Ags encountered in the anterior chamber of the eye—a phenomenon termed anterior chamber-associated immune deviation (ACAID). The induction of ACAID requires the participation of three cell populations: the ocular ACAID APC, the splenic B cell, and the splenic T cell. Because B cells have been implicated in tolerogenic Ag presentation in other systems, we hypothesized that B cells were responsible for the induction of regulatory T cells in ACAID. The central hypothesis for this study is that APC from the eye migrate to the spleen where they release antigenic peptides (OVA) that are captured and presented to T cells by splenic B cells. A combination of in vitro and in vivo studies demonstrated that splenic B cells, incubated with ACAID APC in vitro, were capable of inducing ACAID when transferred to naive mice. The induction of ACAID required the normal expression of β2-microglobulin on both the B cell and ACAID APC, but not on the T suppressor cells. Moreover, the induction of ACAID regulatory cells required histocompatibility between the B cells and regulatory T cells at the TL/Qa region. The results indicate that: 1) B cells are necessary for the induction of ACAID; 2) ACAID B cells do not directly suppress the expression of delayed-type hypersensitivity; and 3) the induction of Ag-specific regulatory T cells by ACAID B cells requires histocompatibility at the TL/Qa region.

A Case for Regulatory B Cells

“…The presence of such a regulatory mechanism is supported by a recent finding that both impairment of B cell activation and decrease in CD8 ϩ T cells is associated with the exacerbation of chronic intestinal inflammation observed in G␣i2 KO mice (89). Furthermore, B cells have been shown to induce such Tregs in a ␤ 2 -microglobulin-dependent fashion at the ocular immune privilege site (90). Therefore, Bregs directly or indirectly interact with several immune cell subsets to control immune responses.…”

Peripheral Tolerance Via the Anterior Chamber of the Eye: Role of B Cells in MHC Class I and II Antigen Presentation

“…A combination of in vitro and in vivo studies has shown that the induction of ACAID begins when F4/ 80 ϩ ocular APCs migrate to the spleen where they release Ag, which is captured and processed by splenic B cells (15,16). These studies also demonstrated that antigenic moieties are released from F4/80 ϩ ocular APCs and captured via the BCR on the splenic B cells, internalized, and processed in acidified lysosomes before being presented to T cells (16).…”

Mesenteric B cells centrally inhibit CD4+T cell colitis through interaction with regulatory T cell subsets

“…One candidate regulatory subset is the CD8 ϩ T cell population recognizing the invariant MHC class I molecule Qa-1 (HLA-E in human), which is expressed at high levels on certain B cell subpopulations. Qa-1 recognition may include mCD94͞ NKG2A (40) and induces negative regulatory activity in experimental autoimmune encephalomyelitis, oral tolerance, and B cell-dependent ocular tolerance (14,21,41). Another candidate is intestinal CD4 ϩ CD8␣ ϩ DP T cells, because they were expanded during B cell-mediated protection.…”

“…In mouse models of oral tolerance, B cells are important for maintenance of a protective cytokine microenvironment in gut-associated lymphoid tissue (13). Similarly, B cells were also required for efficient induction of antigen-specific T cell unresponsiveness in the ocular anterior chamber (14,15) and in the lung in the context of respiratory allergen (16). B cells also attenuate immune responses in certain autoimmune models.…”

“…In collagen-induced chronic arthritis, B cells from arthritogenic splenocytes treated in vitro with anti-CD40 inhibit arthritis in an IL-10-dependent manner (19). B cell immunoregulation typically required their intrinsic expression of IL-10 (11,17,19,20) and, in some cases, the expression of certain invariant class I MHC molecules (11,14,15,21). These observations introduce important questions about the developmental origin of protective B cell subsets and the cellular interactions through which they contribute to immunoregulation by regulatory T cell populations.…”