Paradoxical IgA immunity in CD4-deficient mice. Lack of cholera toxin-specific protective immunity despite normal gut mucosal IgA differentiation.
Using normal and CD4 gene-targeted (CD4-/-) mice, we asked whether mucosal immune responses and IgA B cell differentiation require the presence of CD4+ T helper cells. We found that CD4-/- mice had numerous B cell germinal centers in Peyer's patches and other gut-associated lymphoid tissues. Membrane IgA+ B cells were found to co-localize to germinal center areas and CD4-CD8- double negative CD3+ T cells had replaced CD4+ T cells in the follicular areas of the Peyer's patches. CD4-/- mice had normal levels of IgA-producing cells in gut-associated lymphoid tissues, and gut lavage contained unaltered levels of total IgA. However, despite T cell help for IgA B cell differentiation, CD4-/- mice did not respond with Ag-specific intestinal IgA following oral immunization with the powerful mucosal immunogen cholera toxin (CT). By contrast, these mice demonstrated serum alpha-CT IgG following oral immunization, suggesting that double negative CD3+ T cells provided some help for systemic immune responses after oral immunization. Perorally immunized CD4-/- mice were completely unprotected against CT-induced diarrhea while both normal and CD8-/- mice were well protected and also demonstrated high levels of gut mucosal alpha-CT IgA. After reconstitution of the CD4-/- mice by adoptive transfer of naive mesenteric lymph node CD4+ T cells, the mice acquired the ability to respond with specific mucosal immune responses following oral immunization and also developed resistance against CT-induced diarrhea. Thus, paradoxically, although IgA B cell differentiation appears to proceed normally in CD4-/- mice, specific gut mucosal immune responses are grossly impaired in the absence of CD4+ T cells.
Hörnquist
C E
CE
Department of Medical Microbiology and Immunology, University of Göteborg, Sweden.
Ekman
L
L
Grdic
K D
KD
Schön
K
K
Lycke
N Y
NY
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics* / Q000276:immunology; D002454:Cell Differentiation; D017353:Gene Deletion; D007111:Immunity, Cellular; D007070:Immunoglobulin A / Q000096:biosynthesis*; D016130:Immunophenotyping; D007422:Intestines / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology*
D015704:CD4 Antigens; D007070:Immunoglobulin A