CD45 and Lymphocyte Function
The B cell antigen receptor (BCR) is almost completely uncoupled from proliferative signals in CD45_/_ B cells (Benatar et al. 1996; Byth et al. 1996), correlating with defects in calcium signalling and in activation of the Erk-2/ pp90-Rsk pathways (Benatar et al. 1996; Cyster et al. 1996). The transition from IgMhi IgDhi cells into the IgMlc IgDhi phenotype is known to require a range of BCR-mediated intracellular signals, including Btk and Vav 1/2 regulation (Doody et al. 2001; Meade et al. 2002), so this maturation defect is most likely explained by the high threshold for BCR signalling in the absence of CD45 at this developmental stage.
Nevertheless, CD45-deficient mice appear to mount normal immune responses to T cell-independent antigens (Kong et al. 1995a), whereas T cell-dependent responses are severely defective (Kong et al. 1995a; Ogilvy et al. 2003). Adoptive transfer studies have also shown that B cells from exon 6-targeted mice (Kong et al. 1995a), as well as from exon 9-targeted mice (N. Holmes, unpublished), are capable of isotype switching in response to T-dependent antigens, providing T cells are present from CD45+/+ mice. Therefore the defect in antigenic responses in CD45-deficient mice is localised to the T cell compartment.
As a result of the shifts in the thresholds of selection events during T cell differentiation in the CD45_/_ thymus, self major histocompatibility complex peptides (MHC-peptides) that would normally have caused deletion of self-reactive TCRs now result instead in positive selection, leading to a high proportion of T cells expressing autoreactive TCRs (Trop et al. 2000). However, the development of autoimmunity in CD45_/_ mice is not as aggressive as this finding might suggest, presumably because the few T cells that exit to the periphery are markedly non-responsive to antigenic stimulation. TCR stimulation in CD45_/_ purified mature peripheral T cells results in virtually no proliferation (Stone et al. 1997) and the production of cytokines such as interleukin-2, interleukin-4 and interleukin-10 (IL-2, IL-4 and IL-10) is also much reduced (L. Perry and D.R. Alexander, unpublished). Therefore the results so far indicate that CD45-deficient mature T cells are remarkably non-responsive to stimulation, although the generation of a normal mature T cell repertoire by conditional silencing of the CD45 gene will be important in order to distinguish clearly between the consequences of aberrant development and defects caused directly by the absence of the CD45 molecule.
Was this article helpful?