Functional activity of murine CD44 variant isoforms in allergic and delayed type hypersensitivity

Abstract

There is ample evidence that the family of CD44 glycoproteins is involved in homing, maturation and activation of lymphocytes. Furthermore, recent evidence suggests that CD44 splice variants are particularly involved in the process of lymphocyte activation whereby it was hypothesized that different isoforms may fulfill distinct functions. We here addressed the question of CD44v6 and CD44v7 being involved in TH1 and TH2 reactions using as model systems for TH1 activation a TNBS-induced colitis and a DNFB-induced DTH reaction and for TH2 activation a FITC-induced allergic dermatitis. With the exception of a small subpopulation of lymphocytes in Peyer's patches, expression of neither CD44v6 nor CD44v7 was noted in the absence of an antigenic stimulus. Both CD44 variant exons are transiently detected on T lymphocytes during mounting of an immune response. In vitro studies revealed that antibodies against both CD44v6 and CD44v7 inhibited lymphocyte proliferation and cytokine production. Based on these findings the efficiency of anti-CD44v6 and anti-CD44v7 treatment was evaluated in vivo in TH1 and TH2 dependent autoimmune and DTH reactions. Anti-CD44v7 completely abrogated development of a death promoting colitis and anti-CD44v6 as well as anti-CD44v7 significantly mitigated the DNFB-induced, TH1-mediated DTH reactions, while only anti-CD44v7 interfered with a FITC-induced, TH2-mediated allergic contact dermatitis. The in vitro analysis of cytokine producing cells supported the assumption. In conclusion, it could be demonstrated that CD44v6 and CD44v7 are differentially involved in TH1 and TH2 activation and, most importantly, a TH1-mediated autoimmune disease could be prevented by local application of anti-CD44v7