Abstract
Deficient immunoregulation by CD4+ T cells is an important susceptibility trait for inflammatory bowel disease, but the role of other regulatory cell types is less understood. This study addresses the role and mechanistic interaction of B cells and CD8+ T cells in controlling immune-mediated colitis. The genetic requirements for B cells and CD8+ T cells to confer protective immunoregulation were assessed by cotransfer with colitogenic Galphai2-/- T cells into immune-deficient mice. Disease activity in Galphai2-/- T cell recipients was evaluated by CD4+ T intestinal lymphocyte abundance, cytokine production levels, and large intestine histology. B cells deficient in B7.1/B7.2, CD40, major histocompatibility complex (MHC) II (Abb), or native B cell antigen receptor (MD4) were competent for colitis protection. However, transporter-1-deficient B cells failed to protect, indicating a requirement for peptide MHC I presentation to CD8+ T cells. CD8+ T cells deficient in native T cell receptor repertoire (OT-1) or cytolysis (perforin-/-) also were nonprotective. These finding reveal an integrated role for antigen-specific perforin-dependent CD8+ T cell cytotoxicity in colitis immunoregulatory and its efficient induction by a subset of mesenteric B lymphocytes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Adoptive Transfer
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Animals
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Antigen Presentation*
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Antigens / genetics
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Antigens / metabolism*
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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B7-1 Antigen / metabolism
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B7-2 Antigen / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD40 Antigens / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / transplantation
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Colitis / immunology*
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Colitis / metabolism
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Colitis / pathology
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Colitis / prevention & control
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Cytokines / metabolism
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Cytotoxicity, Immunologic*
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Disease Models, Animal
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Female
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GTP-Binding Protein alpha Subunit, Gi2 / genetics
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GTP-Binding Protein alpha Subunit, Gi2 / metabolism
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Histocompatibility Antigens Class II / metabolism
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Intestine, Large / immunology*
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Intestine, Large / metabolism
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Intestine, Large / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Perforin / genetics
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Perforin / metabolism
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Receptors, Antigen, B-Cell / metabolism
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters
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Antigens
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B7-1 Antigen
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B7-2 Antigen
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CD40 Antigens
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Cytokines
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Histocompatibility Antigens Class II
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Receptors, Antigen, B-Cell
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Tap1 protein, mouse
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Perforin
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GTP-Binding Protein alpha Subunit, Gi2
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Gnai2 protein, mouse