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 TNFalpha, IFN-gamma, 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-gamma+ dendritic cells (DCs) were also significantly higher in M. avium paratuberculosis-challenged mice, than compared to control mice.


CONCLUSIONS
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.
Department of Microbiology, Biochemistry, & Immunology, Morehouse School of Medicine, Atlanta, GA, USA. usingh@gw.med.sc.edu
Udai P
UP
Singh
Rajesh
R
Singh
Shailesh
S
Singh
Russell K
RK
Karls
Frederick D
FD
Quinn
Dennis D
DD
Taub
James W
JW
Lillard
D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000276:immunology / Q000378:metabolism; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000032:analysis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000907:Antibodies, Bacterial; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D054367:Receptors, CXCR3; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma