CD22 Expression Mediates the Regulatory Functions of Peritoneal B-1a Cells during the Remission Phase of Contact Hypersensitivity Reactions

Abstract

While contact hypersensitivity (CHS) has been considered a prototype of T cell-mediated immune reactions, recently a significant contribution of regulatory B cell subsets in the suppression of CHS has been demonstrated. CD22, one of the Siglecs, is a B cell-specific molecule that negatively regulates B cell receptor signaling. To clarify the roles of B cells in CHS, CHS in CD22-/- mice was investigated. CD22-/- mice showed delayed recovery from CHS reactions compared with wild type mice. Transfer of wild type peritoneal B-1a cells reversed the prolonged CHS reaction seen in CD22-/- mice, and this was blocked by the simultaneous injection with IL-10 receptor Ab. While CD22-/- peritoneal B-1a cells were capable of producing IL-10 at wild type levels, intraperitoneal injection of differentially labeled wild type/CD22-/- B cells demonstrated that a smaller number of CD22-/- B cells resided in lymphoid organs 5 days after CHS elicitation, suggesting a defect in survival or retention in activated CD22-/- peritoneal B-1 cells. Thus, our current study reveals a regulatory role for peritoneal B-1a cells in CHS. Two distinct regulatory B cell subsets cooperatively inhibit CHS responses. While splenic CD1dhiCD5+ B cells have a crucial role in suppressing the acute exacerbating phase of CHS, peritoneal B-1a cells are likely to suppress the late remission phase as “regulatory B cells”. CD22 deficiency results in disturbed CHS remission by impaired retention or survival of peritoneal B-1a cells that migrate into lymphoid organs.

IL-10+ Innate-like B Cells Are Part of the Skin Immune System and Require α4β1 Integrin To Migrate between the Peritoneum and Inflamed Skin

“…Our findings are consistent with the non-redundant role of B cells and/or B cell-derived IL-10 in limiting skin inflammation in human psoriasis (16-18) and mouse models of cutaneous hypersensitivity and psoriasis-like inflammation (12, 34, 50). Importantly, human psoriasis is associated with low levels of cutaneous IL-10 and clinically responsive to treatment with dermal IL-10 (51), stressing the importance of cutaneously produced IL-10 in limiting skin inflammation.…”

“…IL-10 + peritoneal B1 cells suppress skin inflammation (12) and we found IL-10 producing B1-phenotype cells in human and mouse skin (Figs. 2B-D and 3E and F).…”

“…For example, IL-10 + peritoneal B1 cells suppress inflammation in mouse models of cutaneous hypersensitivity and colitis (12, 13). IL-10 producing B cells in general have recently received wide attention due to their ability to limit T cell-mediated inflammation in both the skin and non-cutaneous sites, such as the joints, central nervous system and colon, mainly by suppressing T cells and other cell types in lymphoid tissues (reviewed in (14, 15)).…”

Regulatory functions of innate-like B cells

“…1 B1a cells 47 played suppressive roles during the late remission phase. In both situations, Bregs exerted their regulatory roles in an IL-10-dependent manner, and specifically, the identification of CD1d hi CD5…”

Regulatory B cells in skin and connective tissue diseases

“…Other organ-specific autoimmune disease models, especially EAE [17,18,32,33] and colitis [19,34], have also provided important mechanisms for how The role of B-1 cells in CHS is still controversial, however. While our study, as described above [35], suggests that B-1 cells have a protective role, Tsuji and colleagues demonstrate a promoting, rather than inhibitory, role for peritoneal B-1 cells in CHS [36]. Using Btk-defective xid mice on a CBA background, they demonstrated that Ag-specific IgM Abs from peritoneal B-1 cells are required for the recruitment of effector T cells in the early elicitation phase [36].…”