B cell function in mice transgenic for mCTLA4-H gamma 1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells.

Abstract

SumlnaryThis report outlines the B cell phenotype of transgenic mice that overexpresses the mouse CTLA-4-humanyl (mCTLA4-H'y1) protein. Despite the fact that these mice prime CD4 + T cells (Ronchese, F., B. Housemann, S. Hubele, and P. Lane. 1994. J. Exp. Med. 179:809), antibody responses to T-dependent antigens are severely impaired. In contrast, T-independent responses are normal which suggests mCTLA4-H'y1 does not act directly on B cells, but acts indirectly by impairing T cell help. The impaired antibody defect is associated with impaired class switching, with low total immunoglobulin (Ig)G and antigen-specific IgG responses, and an absence of germinal center formation in spleen and lymph nodes but not gut-associated tissues. The defective germinal center formation is associated with a reduction in the degree of somatic mutation in hybridomas made from transgenic mice in comparison with those made from normal mice. It seems likely that mCTLA4-H'y1 exerts its effect by blocking an interaction between T and B cells that induce T cell help for B cells.

Cutting Edge: Critical Role of Inducible Costimulator in Germinal Center Reactions

“…CD28 is critical for T cell activation and differentiation and hence also for GC in response to protein Ag (4,5). ICOS is a novel CD28-related costimulator that is expressed by activated T cells (6,7).…”

Strong Differential Regulation of Serum and Mucosal IgA Responses as Revealed in CD28-Deficient Mice Using Cholera Toxin Adjuvant

“…When indicated experiments were conducted with mice generated by crossing and intercrossing the CTLA4-H␥1 Tg onto the CD28 Ϫ/Ϫ mice. The genotype of the CD28 Ϫ/Ϫ and CTLA4-H␥1 positive or negative mice were confirmed by PCR using appropriate primers, by FACS analysis of phenotype using CD28-specific Abs, and by ELISA for detection of the CTLA4-H␥1 protein, as previously described (19,28). All experiments were conducted with sex-matched, 8-to 14-wk-old mice.…”

“…These mice exhibited GC formations in PP, but not in the spleen or peripheral lymph nodes. In contrast to the impaired total IgG levels in serum, total IgA production in the gut was normal compared with wild-type (WT) mice (19,20). However, despite the seemingly unaffected IgA-inductive sites and the normal total IgA levels in these mice, they responded poorly to oral immunizations given together with cholera toxin (CT) adjuvant.…”

Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells

“…Signaling through CD28 and OX40 upregulates mRNA for CXCR-5 in vitro 4, and CD28 signaling is required to generate the CXCR-5 subset of memory CD4 T cells in vivo 5. The lack of CXCR-5–positive CD4 T cells in CD28-deficient mice is directly correlated with their failure to form GCs 16. Whereas CD28 signaling is absolutely required for the generation of CD4 T cell help for GCs, an IL-12–dependent Th1 inflammatory CD4 immune response to the intracellular pathogen Leishmania is not CD28 dependent 17.…”