CXCL10(+ )T cells and NK cells assist in the recruitment and activation of CXCR3(+ )and CXCL11(+ )leukocytes during Mycobacteria-enhanced colitis

BACKGROUND: The role of Mycobacteria in the etiology of Crohn's disease (CD) has been a contentious subject for many years. Recently, our laboratory showed that spontaneous colitis in IL-10(-/- )mice is driven in part by antigens (Ags) conserved in Mycobacteria. The present study dissects some of the common cellular and molecular mechanism that drive Mycobacteria-mediated and spontaneous colitis in IL-10(-/- )mice. RESULTS: We show that serum from inflammatory bowel disease (IBD) patients contain significantly higher levels of Mycobacterium avium paratuberculosis-specific IgG1 and IgG2 antibodies (Abs), serum amyloid A (SAA) as well as CXCR3 ligands than serum from healthy donors. To study the cellular mechanisms of Mycobacteria-associated colitis, pathogen-free IL-10(-/- )mice were given heat-killed or live M. avium paratuberculosis. The numbers of mucosal T cells, neutrophils, NK/NKT cells that expressed TNFα, IFN-γ, and/or CXCL10 were significantly higher in mice that received live Mycobacteria than other groups. The numbers of mucosal CXCR3(+), CXCL9(+), CXCL11(+ )and/or IFN-γ(+ )dendritic cells (DCs) were also significantly higher in M. avium paratuberculosis-challenged mice, than compared to control mice. CONCLUSION: The present study shows that CD and UC patients mount significant Mycobacteria-specific IgG1 > IgG2 and CXCR3 ligand responses. Several cellular mechanisms that drive spontaneous colitis also mediate Mycobacteria-enhanced colitis in IL-10(-/- )mice. Similar to IL-10(-/- )mice under conventional housing, we show that Mycobacteria-challenge IL-10(-/- )mice housed under otherwise pathogen-free conditions develop colitis that is driven by CXCR3- and CXCR3 ligand-expressing leukocytes, which underscores another important hallmark and molecular mechanism of colitis. Together, the data show that Mycobacteria-dependent host responses, namely CXCL10(+ )T cells and NK cells, assist in the recruitment and activation of CXCR3(+ )and CXCL11(+ )leukocytes to enhance colitis of susceptible hosts.